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chemoresistance

che·mo·re·sis·tance (kē'mō-rē-zis'tants),

The resistance of bacteria or malignant cells to the inhibiting action of certain chemical substances used in treatment.

 

chemoresistance /che·mo·re·sis·tance/ (-re-zis´tans) specific resistance acquired by cells to the action of certain chemicals.

 

chemoresistance

1 a specific resistance by components of a cell to chemical substances.

2 the resistance of bacteria or a cancer cell to a chemical designed to treat the disorder.

 

chemoresistance

  1. Resistance of cells to the action of a specific therapeutic agent.
  2. Resistance of a particular tumor to chemotherapy; treatment refractory.

 

che·mo·re·sis·tance (kē'mō-rē-zis'tăns)

The state of being resistant to a chemical.

 

 

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References in periodicals archive

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DelMar has demonstrated that VAL-083's anti-tumor activity is unaffected by common mechanisms of chemoresistance in vitro.

US FDA Grants Fast Track Designation to DelMar Pharmaceuticals for VAL-083 in Recurrent Glioblastoma

NEDD4-1 may regulate the proliferation, invasion, migration, and chemoresistance of lung ADC cells through the PI3K/Akt pathway, suggesting that it may be regarded as a therapeutic target for the treatment of lung ADC.

Upregulation of Neural Precursor Cell Expressed Developmentally Downregulated 4-1 is Associated with Poor Prognosis and Chemoresistance in Lung Adenocarcinoma

15,64] Hypoxia-induced autophagy also imparted chemoresistance in HCC cells.

Hypoxia-induced autophagy in hepatocellular carcinoma and anticancer therapy

The poor response to chemotherapy is hypothesized to be due to either chemoresistance commonly seen in neuroendocrine tumors of other sites, or the lack of an appropriately determined regimen.

Neuroendocrine Tumors of the Breast

33 A lower Bax/Bcl-2 ratio is associated with chemoresistance and adverse cytogenetics in AML.

Recent advances in diagnostic and prognostic aspects of acute myeloid leukaemia

Therefore, novel strategies to overcome chemoresistance are urgently required.

Salinomycin enhances doxorubicin sensitivity through reversing the epithelial-mesenchymal transition of cholangiocarcinoma cells by regulating ARK5

The higher urolithin A concentration mixture was most effective at inhibiting the number and size of colon-cancer stem cells and inhibiting the activity of aldehyde dehydrogenase, a marker of chemoresistance.

Pomegranate Improves Markers of Aging

This nanoparticle formulation provides new and promising properties, including overcoming the mechanisms of chemoresistance developed by tumour cells that affect the efficacy of chemotherapy agents.

Onxeo receives Notice of Allowance from USPTO for Livatag in hepatocellular carcinoma

Currently, authors advocate that the recurrence and chemoresistance are the main problems for its treatment.

Expression of CD133, E-cadherin and WWOX in colorectal cancer and related analysis

Dr Gottesman, whose research interests include mechanisms by which cancers become resistant to chemotherapy, reinforced in his keynote address that traditional monolayer cell culture models used to study tumor chemoresistance have proven to be woefully inadequate.

3D Cell Culture experts assemble for inaugural new frontiers in 3D conference hosted by CAAT

53) Although it remains to be elucidated whether the altered metabolism directly affects carcinogenesis or chemoresistance, it seems likely that metabolism plays an important role in reprogramming cancer cells to the pluripotent state.

Getting to the heart of the matter in cancer: novel approaches to targeting cancer stem cells

Immediate and transient phosphorylation of the heat shock protein 27 initiates chemoresistance in prostate cancer cells.

Prostat Kanseri Tedavisinin Gelecegi Apoptotik indukleyicilerde mi?/Does the Future of Prostate Cancer Treatment Lie with Apoptotic Inducers?

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Mechanisms of Chemoresistance in Human Ovarian Cancer at a Glance

Michelle X Liu, David W Chan* and Hextan YS Ngan

 

Department of Obstetrics and Gynaecology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, P.R.China

 

Received date: May 21, 2012; Accepted date: May 21, 2012; Published date: May 24, 2012

 

Citation: Liu MX, Chan DW, Ngan HYS (2012) Mechanisms of Chemoresistance in Human Ovarian Cancer at a Glance. Gynecol Obstet 2:e104. doi: 10.4172/2161-0932.1000e104

 

Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

 

Visit for more related articles at Gynecology & Obstetrics

Abstract

 

Ovarian cancer is one of the most deadly malignancies in women because of its poor prognosis and that a majority of patients are diagnosed at advanced stage. Therefore, chemotherapy becomes the most important treatment option in most ovarian cancer cases. However, chemoresistance in relapsed cases is the major obstacle for the clinical management of this disease. Mounting evidences have suggested the de novo (intrinsic) and acquired (extrinsic) chemoresistance are two major underlying mechanisms occurring in human cancers. The de novo chemoresistance is attributed to the existence of cancer stem cells, while the genetic and/or epigenetic alterations in dysregulation of oncogenes or tumor suppressor genes contribute to the acquired chemoresistance. In this review, we will summarize and discuss the recent findings of the above mechanisms in chemoresistance and particularly, we will focus on the significance of putative miRNAs expressions and their associated signaling regulations in the development of acquired chemoresistance in ovarian cancer.

 

Keywords

 

De novo and acquired chemoresistance; Genetic and epigenetic alterations; MicroRNA; Signaling pathways; Ovarian cancer

Editorial

 

Ovarian cancer is one of the most leading fetal gynaecological malignance in women worldwide [1,2]. The high mortality rate of this disease is because of its poor prognosis and that approximately 75% of the patients are diagnosed at advanced stages (FIGO stages III and IV). Therefore, adjuvant chemotherapy is necessary for the clinical management of patients with advanced tumors [3]. Platinumbased combination chemotherapy is the standard first-line strategy for ovarian cancer patients. Although initial treatment achieves high percentage in responses, most of the patients will eventually develop resistance to anti-cancer drugs [4,5]. Therefore, chemoresistance is the major clinical obstacle for the treatment of ovarian cancer patients nowadays. Mounting evidences have documented that de novo (intrinsic) and acquired (extrinsic) chemoresistance are two major most likely mechanisms in various human cancers. However, the precise mechanism for chemoresistance in ovarian cancer remains unclear.

 

The de novo chemoresistance, also called as intrinsic chemoresistance, refers to cancer cells that are resistant to chemotherapeutic drugs from the very beginning of anti-cancer drug treatment. This type of chemoresistance originates from cells which have already had capacities of drug-resistance such as limiting drugs uptake, enhancing efflux, or activating detoxification of drugs [6]. Previous studies reported that the aberrant expressions of certain crucial proteins could lead to intrinsic chemoresistance. For instance, the reduced expression of BNIP3 (Bcl2/adenovirus E1B 19 kDa protein interacting protein) and increased expression of ISG15 (Interferon-Stimulated Gene 15) were associated with intrinsic gemcitabine resistance in pancreatic cancer patients [7,8]. Up to date, researchers have summarized that this subset of tumor cells with resistant properties against anti-cancer drugs is Cancer Stem Cells (CSC), which are also known as tumor initiating cells. This type of cells shows high cell survival rate under chemotherapeutic challenge, faster proliferation and high spreading capacity. Researchers believe such CSCs are responsible for the abilities of tumorigenesis, selfrenewal, differentiation and chemo/radio-resistance [9,10]. A very recent report showed that MYC-driven murine tumors contained a subset of cells that refluxed Hoechst 33342. Such onco-genotype of the hepatic tumor could promote a specific mechanism of chemoresistance that contributed to the survival of hepatic CSCs [11]. This evidence suggests that CSCs contribute to intrinsic chemoresistance in human cancer. However, the characteristics of CSCs and their functions in chemoresistance of a wide range cancer types need more evidences to prove and elucidate [12-14].

 

On the other hand, the mechanism of acquired chemoresistance, which is also called extrinsic chemoresistance, includes genetic and epigenetic alternations of crucial genes in cancer cells during the repetitive treatment of chemotherapy. The genetic and epigenetic changes in cells may gradually induce cancer cells to adapt the apoptotic stresses of anti-cancer drugs [15]. In ovarian cancer, the first-line chemotherapy with a combination of platinum-paclitaxel yields response rates of more than 80%; with 40–60% cases have complete response in advanced ovarian cancer. However, the median progression-free survival is only 18 months as most of these patients relapse ultimately [16]. Re-treating these patients with the same drugs (carboplatin and paclitaxel) always confers response rates of around 50% in tumors that relapse more than 12 months after initial treatment. But this falls to 10–20% when the treatment-free interval is less than 6 months [17]. This indicates that the chemoresistance of ovarian cancer is likely due to the existence of acquired chemoresistance.

 

Although the underlying mechanism leading to acquired chemoresistance is still unclear, numerous studies have documented that genetic or epigenetic alterations are frequently occurred and are the cause of chemorsistance development in cancers. The reasons are attributed to the mechanisms of most anti-cancer drugs for inhibiting cancer cell growth through impairing DNA synthesis, damaging the DNA in the nucleus or breaking down the mitotic spindles of the cells. These effects could cause genetic and epigenetic changes in gene expressions. Genetic changes refer to the changes in DNA sequence, including mutation, deletion, amplification, translocation, and so on. When these changes happen to genes, such as TP53, RB1 and KRAS, which are significant for controlling cell cycle, proliferation, survival and apoptosis etc, they make cancer cells aggressive and chemoresistant [18-20]. Recently, abundant evidences have showed that the genetic alternations could be one of the causes of the acquired resistance in human ovarian cancer. For example, Shim et al. [21] reported that an elevation of a transcription factor NF-E2-Related Factor-2 (NRF2) activity might be a determining factor for resistance to doxorubicin in ovarian carcinoma cell lines and the adaptive activation of the NRF2 system could participate in the development of acquired resistance to anthracycline therapy. Fu et al. [22] found that the enhanced expression of Glycogen Synthase Kinase-3α (GSK-3α) was associated with acquired resistance to paclitaxel in ovarian carcinoma cells. Moreover, Ong et al. [23] using microarray analysis in a newly established arsenic-resistant ovarian cancer cell line OVCAR-3/AsR revealed that there was a dysregulation of multiple genes associated with the development of acquired chemoresistance to As(2)O(3) and increased tumor aggressiveness.

 

In the past few decades, emerging evidences have documented that the epigenetic alterations could be the novel mechanism leading to the acquired chemoresistance. Epigenetic changes, including DNA methylation, histone modifications and microRNA regulation, regulate crucial gene expressions critically in the development of drug-resistance [24-26]. Initially, researchers have focused on DNA methylation and histone modifications for gene expression regulation. This is because DNA hypermethylation, together with histone methylation and/ or histone deacetylation, in the promoter region cause chromosome remodeling and further inhibit the binding of transcription factors to the promoter region. This induces gene silence in the transcriptional level [27,28]. For instance, hypermethylation in the transcription factor AP2E downregulated its expression, induced overexpression of DKK4 and further made colorectal cancer patients suffer to ineffectiveness to fluorouracil-based chemotherapy [29]. In ovarian cancer cells, MutL Hhomolog 1 (MLH1) and TAp73 are two well-known examples silenced by methylation and such gene silencing confers ovarian cancer cells to be acquired drug resistance [30,31]. Indeed, the recent comprehensive studies in methylation have been conducted and several drugs, such as 5-azacitidine (Aza) and hydralazine, have been used in clinical trials for tackling chemoresistance in human cancers [32,33], suggesting the DNA methylation is one of the major causes in chemoresistance.

 

Recently, researchers have found another type of epigenetic changes, microRNA (miRNA) playing a crucial role in gene regulation and chemoresistance. MiRNAs refer to a group of small, non-coding RNAs that bind to the 3’UTR of their target mRNAs under base complementarity via the miRNAs seed sequence. This induces the target mRNA degradation or translational repression, depending on the complementary level of the binding between miRNA and its target mRNAs [34,35]. Indeed, it’s well known that the regulation of miRNA plays an important role in the cell development and differentiation during embryonic development. In contrast, deregulation of miRNAs usually contributes to various diseases including cancers [36,37]. Emerging evidences have suggested that the deregulation of miRNAs is closely associated with the acquired chemoresistance in various human cancers including ovarian cancer. For example, up-regulation of miR- 21 enforced its function in HER2+ BT474, SKBR3, and MDA-MB-453 breast cancer cells that were induced to the acquired trastuzumab resistance by long-term exposure to trastuzumab antibody [38]. In addition, loss of MiR-181a and miR-630 expressions might inhibit cisplatin-induced cancer cell death in Non Small Cell Lung Cancer (NSLC) [39]. Moreover, a recent study reported that the upregulation of miR-214 and miR-376c induced cell proliferation, cell survival and cisplatin resistance in ovarian cancer [40,41]. Therefore, further investigation of miRNA deregulation is a need to unveil the mechanism of chemoresistance in human cancers including ovarian cancer.

 

As the base complementarity between miRNA and its binding to the 3’UTR of mRNAs is not necessary to be 100%, one miRNA may regulate numerous target mRNAs. Hence, one miRNA may be involved in governing a network of signaling pathways such as the TGF-β, WNT and EGF signaling cascades. Considering these pathways act as very important roles in regulating cell proliferation, apoptosis, DNA repair etc., the deregulation of miRNAs expressions could cause dysfunction of these pathways in regulating cellular physiology and properties including increased resistance to anti-cancer drugs induced cell apoptosis [42-44]. There are several well-known pathways regulated by miRNAs found in ovarian cancer chemoresistance, such as PI3K/ AKT/mTOR and Phosphatase and Tensin Homolog (PTEN) signaling cascades [45,46]. For example, Nagaraja et al. [47] found that miR-22 and miR-100 repressed AKT/mTOR signaling and enhanced sensitivity to the rapamycin analog RAD001 (everolimus) in clear cell ovarian cancer. In addition, Fu et al. [48] also found that miR-93 was inversely correlated with PTEN expression in CDDP-sensitive and induced resistant human ovarian cancer cells by activation of AKT signaling pathway. Apart from the above pathways, NOTCH signaling is one of the most famous pathways for the development of chemoresistance in various human cancers including ovarian cancer. The conserved ligand-receptor NOTCH, governing its signaling factors such as the HES family and the HEY family, plays critical roles in cell proliferation, survival, apoptosis as well as resistance to anti-cancer drugs [49-51]. Numerous reports found that miR-34 participated in the Notch pathway regulation and involved in the acquired drug resistance in prostate cancer and breast cancer, suggesting that miRNA mediated NOTCH signaling activity was involved in chemoresistance of cancers [52,53]. NOTCH pathway contains abundant signaling factors for regulating its gene expression and cross-talking with Wnt and Hedgehog pathways, indicating miRNAs modulate not only NOTCH but also other signaling pathways [54,55]. Apart from NOTCH pathway, recent findings also raise the importance of FOXM1 transcription factor network in human cancers including ovarian cancer [49]. Our laboratory have previously revealed that the aberrant activation of FOXM1 signaling cascade triggered cell migration in ovarian cancer cells, suggesting that FOXM1 was associated with aggressive chemoresistant ovarian cancer [56]. Therefore, further investigations in miRNAs regulating of NOTCH and FOXM1 pathways may provide new insights in the mechanism of chemoresistance and assist in exploring molecular therapeutic strategies in ovarian cancer.

 

In conclusion, although recent studies have suggested that the acquired resistant mechanism is the major chemoresistance in ovarian cancer, further investigations to support this notion is needed. Moreover, the understanding of miRNA regulated signaling pathways controlling cell proliferation, apoptosis, DNA repair etc. such as NOTCH and FOXM1 pathways may provide valuable insights in the molecular mechanisms of the development of acquired chemoresistance.

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Mechanisms Involved in Chemoresistance in Ovarian Cancer

Author links open overlay panelKar-SanLingGin-DenChenHorng-JyhTsaiMaw-ShengLeePo-HuiWangFu-ShingLiua

https://doi.org/10.1016/S1028-4559(09)60143-1

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Open Access funded by Taiwan Association of Obstetrics & Gynecology

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Summary

 

Chemotherapy is a major treatment modality for ovarian cancer, but chemoresistance is a clinical problem that compromises the efficiency of treatment and finally results in treatment failure. The development of resistance to chemotherapeutic agents might be related to multiple mechanisms such as alterations in drug transport, changes in cellular proteins involved in detoxification, altered drug target, changes in DNA repair mechanisms, and increased tolerance to drug-induced DNA damage. This article is a summary of the various mechanisms that are involved in chemoresistance in ovarian cancer.

 

Ovarian Cancer Chemoresistance

 

   Authors

   Authors and affiliations

 

   Sharon O'TooleEmail authorJohn O'Leary

 

   Sharon O'Toole

       1Email author

   John O'Leary

       1

 

   1.Departments of Obstetrics and Gynaecology/HistopathologyTrinity College Dublin, Trinity Centre for Health SciencesDublinIreland

 

Reference work entry

First Online: 10 March 2017

DOI: https://doi.org/10.1007/978-3-642-16483-5_6930

 

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Definition

 

Ovarian cancer is the leading cause of death from gynecological malignancy in the Western world. Worldwide there are more than 225,000 new cases of ovarian cancer each year, accounting for around 4% of all cancers diagnosed in women. Ovarian cancer has remained the most challenging of all the gynecological malignancies for two reasons. First,  early-stage ovarian cancer, which has a good prognosis, cannot be detected easily. Second, standard chemotherapy approaches such as paclitaxel and carboplatin often fail and patients develop recurrent chemoresistant disease. Chemoresistance is a therapeutic problem that severely limits successful treatment outcomes for many human cancers. This is particularly true of ovarian cancer, where the development of resistance is a common occurrence.

Characteristics

Symptoms and Treatment of Ovarian Cancer

 

The symptoms of ovarian cancer are nonspecific and often occur when the disease is already spread throughout the abdominal cavity. Abdominal discomfort or vague pain, abdominal fullness, bowel habit changes, early satiety, dyspepsia, and bloating are frequent presenting symptoms.  Early-stage ovarian cancer is usually asymptomatic, and the diagnosis is often incidental. Early-stage ovarian cancer has up to a 90% 5-year overall survival rate, whereas late stage cancers have less than a 30% 5-year survival rate. Current detection strategies include ultrasound and  CA-125; however, both have their drawbacks resulting in the lack of a reliable sensitive screening test for ovarian cancer.

 

The first step in the management of patients with  epithelial ovarian cancer is an accurate diagnosis and thorough staging, with optimal surgical  cytoreduction of metastatic disease, also referred to as surgical debulking. Postoperative chemotherapy is then administered to patients with a significant risk of recurrence. From the 1960s to the present, primary chemotherapy for advanced ovarian cancer has evolved from single  alkylating agents to cisplatin and cisplatin-based combinations, followed by incorporation of paclitaxel and substitution of carboplatin for cisplatin. Currently, platinum drugs ( Platinum Complexes) in combination with taxanes are the most active agents in epithelial ovarian cancer. Despite its efficacy,  drug resistance to chemotherapy, both intrinsic and acquired, is a hurdle that significantly hinders successful treatment outcomes. Primary chemoresistance to platinum-based chemotherapy occurs in as many as 25% of patients, and a further 50–60% have tumors that will acquire “platinum resistance” at some point during treatment. Clinicians generally treat ovarian carcinomas as a single entity despite pathological classification ( Ovarian Cancer Pathology). The decision to give chemotherapy is generally based on stage and grade. Oncologists have noted that the dismal response rate of clear cell and mucinous carcinomas to chemotherapy (15%) contrasts sharply with that of high-grade serous carcinomas (80%). With the exception of clear cell carcinoma, histology has not been a factor used to determine chemotherapy management. Despite improved outcomes for many ovarian cancer patients over the past decade, the long term survival has not been yet uniformly improved. For this reason, identification of prognostic factors predictive of clinical outcome in patients with ovarian cancer may facilitate the design of more targeted, tailored therapeutic regimens in the future

Chemoresistant Disease

 

The management of patients with recurrent ovarian cancer remains an area of active investigation.  Salvage chemotherapy is important in ovarian cancer because many patients respond to several salvage regimens. With the widespread adoption of  adjuvant platinum-based combination chemotherapy for advanced-stage disease, the relapse-free interval after completion of that therapy (or the platinum-free interval) has been recognized as a predictor of the likelihood of subsequent response to chemotherapy. Patients with a relapse-free interval of more than 6 months (platinum sensitive) have a higher probability of responding to platinum again and to other chemotherapeutics. Platinum-resistant disease included disease that relapsed within 6 months of adjuvant therapy or disease that progressed while the patient was taking platinum in the salvage setting.

 

For patients with platinum-resistant disease, the selection of several agents have shown some activity, including  topotecan, liposomal doxorubicin, taxanes, gemcitabine, oral etoposide, altretamine (hexamethylmelamine), and ifosfamide. The selection of which individual agent to use has been primarily based on toxicity considerations. These agents usually have response rates of approximately 5–20%, possibly because they ignore certain aspects of tumor biology. With these rather low response rates, patients frequently have to make a decision about either continuing chemotherapy or receiving  supportive care only. Assessment of chemotherapy sensitivity and resistance assays in the front-line setting identified no assays for which the evidence base was sufficient to support their use in oncology practice outside a clinical trial setting.

 

As a global strategy for second- or third-line treatment does not exist, initial efforts have been made to evaluate chemosensitivity assays for patients with recurrent disease. Also, models have been proposed for prospective validation of treatment selection criteria, hopefully to be applied to future randomized trials of assay-directed therapy.

Mechanisms of Platinum Resistance

 

Platinum-based drugs ( Platinum Complexes) generally work by forming intra- or interstrand cross-links ( Interstrand Cross Link) in DNA that begins the process of  cell cycle arrest and results in tumor cell apoptosis. Resistance is generally due to a combination of mechanisms, some resulting in reduced DNA damage and others following DNA damage. Platinum drugs enter cells using either  transporters, (a significant one being the copper transporter CTR1) or by passive diffusion. Loss of CTR1 results in less platinum drugs entering cells and consequently drug resistance. Once inside cells, platinum drugs are activated by the addition of water molecules to form a chemically reactive aqua species. This is facilitated by the relatively low chloride concentrations that are found within cells. In the  cytoplasm, the activated aqua species preferentially reacts with species containing high sulfur levels by virtue of their containing many cysteine or methionine amino acids. These species include the tripeptide glutathione or metallothioneins. In some platinum-resistant cancer cells, glutathione and metallothionein levels are relatively high, so activated platinum is effectively “mopped up” in the cytoplasm before DNA binding can occur, thereby causing resistance. Active export of platinum from the cells through the copper exporters ATP7A and ATP7B as well as through the glutathione S-conjugate export GS-X pump (also known as MRP2 or ABCC2;  ABC-Transporters) can contribute to platinum drug resistance.

 

Resistance occurring post-DNA binding may be due to changes in  DNA repair pathways [an increase in nucleotide excision repair (NER) or a loss of DNA  mismatch repair (MMR)]. Conversely, the hypersensitivity of some cell lines to cisplatin is due to defective NER, through loss or reduced expression of NER proteins such as XPG and XPA. Finally, resistance might occur to platinum, and other cancer drugs, through decreased expression or loss of apoptotic signaling pathways as mediated through various proteins such as  p53, anti-apoptotic, and pro-apoptotic members of the Bcl2 family, and JNK ( Jun N-terminal Kinase).

Mechanisms of Taxane Resistance

 

Paclitaxel, a potent drug of natural origin isolated from the bark of the pacific yew, Taxus brevifolia, acts by stabilizing  microtubule (MT) polymers, inhibiting MT depolymerization and changing MT dynamics, leading to mitosis arrest and apoptosis. It also induces post- translational modifications of  tubulin, such as detyrosination or acetylation that accumulate in these stable microtubules. Paclitaxel-treated cells are unable to proceed normally through the cell cycle and arrest in the G2/M phase. As paclitaxel primarily targets polymerized microtubules, an increase in the proportion of unstable microtubules induces paclitaxel resistance.

 

General mechanisms of drug resistance can apply to  taxanes, including overexpression of the ABC/MDR transporter family of proteins, delayed G2/M transition, defective mitotic checkpoints and alterations in apoptosis regulation. More specifically, alterations of microtubules, such as those caused by b-tubulin mutations induce severe taxane resistance. Alternatively, factors that increase the ratio of unstable to stable microtubules induce profound taxane resistance.  Extracellular matrix proteins appear to modulate microtubule stability and alter paclitaxel sensitivity in ovarian cancer. The functional status of p53 can regulate the sensitivity of cancer cells to chemotherapeutic drugs. p53 regulates the sensitivity of antimicrotubule drugs, such as taxanes and Vinca alkaloids, by controlling the expression of proteins that affect the dynamic equilibrium of microtubule assembly.

Circumventing Resistance

 

Unfortunately, in women with advanced disease, cells initially sensitive to chemotherapy can later regrow, and this reflects unacceptably low median overall survival (24–60 months). Apart from the manipulation of doses, schedules, mode of delivery, and combination of existing drugs, the development of new therapeutic approaches represents a challenging priority. Numerous strategies are being pursued. One is to use current high-throughput genomic studies to analyze thousands of genes in the tumors of women with chemosensitive versus chemoresistant disease. The goal of this approach is to be able to predict, at the outset, which women will benefit significantly from standard chemotherapy approaches versus those who should be treated with alternative approaches. Technologic advances that allow us to examine the molecular machinery ( mRNA and  microRNA) driving cancer cells have helped to identify numerous mediators within ovarian cancer cells that can be targeted with new molecular strategies. Examples include agents that block stimulatory growth factor receptors at the cell surface, small molecule inhibitors of signal transduction pathways, approaches that harness specific elements of the immune system that ovarian cancers have successfully suppressed, gene and viral therapy strategies, and antiangiogenesis strategies, covering all aspects of cancer hallmarks.

Cancer Stem Cells in Chemoresistance

 

The role of cancer cells with stem like properties is receiving a lot of attention recently and their role in ovarian cancer and chemoresistance remains to be elucidated. It is widely accepted that extensive self-renewal and differentiation of cancer  stem cells contributes to primary malignancy. Due to this regenerative property, their persistent post-intervention may explain chemoresistance and recurrence in ovarian cancer. Specific targeting of this population of cells could lead to improved treatment and management of this disease.

Conclusions

 

The molecular basis for chemoresistance is largely unknown and there is a continuing requirement to develop new strategies for the treatment of ovarian cancer. The identification of  biomarkers could reduce unnecessary chemotherapy treatment and toxicity, prolong survival, and lead to more effective therapy for ovarian cancer.

References

 

   1.

   Kelland L (2007) The resurgence of platinum-based cancer chemotherapy. Nat Rev Cancer 7:573–584PubMedCrossRefGoogle Scholar

   2.

   Alvero AB, Chen R, Fu HH, Montagna M, Schwartz PE, Rutherford T, Silasi DA, Steffensen KD, Waldstrom M, Visintin I, Mor G (2009) Molecular phenotyping of human ovarian cancer stem cells unravels the mechanisms for repair and chemoresistance. Cell Cycle 8(1):158–166PubMedPubMedCentralCrossRefGoogle Scholar

 

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   O'Toole S., O'Leary J. (2011) Ovarian Cancer Chemoresistance. In: Schwab M. (eds) Encyclopedia of Cancer. Springer, Berlin, Heidelberg

 

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   DOI https://doi.org/10.1007/978-3-642-16483-5 Publisher Name Springer, Berlin, Heidelberg Print ISBN 978-3-642-16482-8 Online ISBN 978-3-642-16483-5 eBook Packages Biomedical and Life Sciences

 

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Int J Biol Sci 2017; 13(6):794-803. doi:10.7150/ijbs.18969

 

Research Paper

Berberine Reverses Hypoxia-induced Chemoresistance in Breast Cancer through the Inhibition of AMPK- HIF-1α

 

Yue Pan1, Dan Shao1, Yawei Zhao1, Fan Zhang1, Xiao Zheng1, Yongfei Tan1, Kan He1, Jing Li1 Corresponding address, Li Chen1, 2 Corresponding address

 

  1. Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun 130021, China;
  2. School of Nursing, Jilin University, Changchun 130020, China.

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions.

How to cite this article:

Pan Y, Shao D, Zhao Y, Zhang F, Zheng X, Tan Y, He K, Li J, Chen L. Berberine Reverses Hypoxia-induced Chemoresistance in Breast Cancer through the Inhibition of AMPK- HIF-1α. Int J Biol Sci 2017; 13(6):794-803. doi:10.7150/ijbs.18969. Available from http://www.ijbs.com/v13p0794.htm

Abstract

 

Breast cancer is the most common type of cancer and the second leading cause of cancer death in American women. Chemoresistance is common and inevitable after a variable period of time. Therefore, chemosensitization is a necessary strategy on drug-resistant breast cancer. In this study, MCF-7 breast cancer cell was cultured under hypoxia for a week to induce the resistance to doxorubincin (DOX). The effect of different doses of berberine, a traditional Chinese medicine, on DOX sensitivity to MFC-7/hypoxia cells was observed. We found that hypoxia increased DOX resistance on breast cancer cells with the AMPK activation. Low-dose berberine could resensitize DOX chemosensitivity in MCF-7/hypoxia cell, however, high-dose berberine directly induced apoptosis. The intriguing fact was that the protein expressions of AMPK and HIF-1α were down-regulated by berberine, either low dose or high dose. But the downstream of HIF-1α occurred the bifurcation dependent on the dosage of berberine: AMPK-HIF-1α-P-gp inactivation played a crucial role on the DOX chemosensitivity of low-dose berberine, while AMPK-HIF-1α downregulaton inducing p53 activation led to apoptosis in high-dose berberine. These results were consistent to the transplanted mice model bearing MCF-7 drug-resistance tumor treated by berberine combined with DOX or high-dose berberine alone. This work shed light on a potentially therapeutic attempt to overcome drug-resistant breast cancer.

 

Keywords: berberine, hypoxia, breast cancer resistance, AMPK, HIF-1α.

Introduction

 

Breast cancer is the most common type of cancer and the second leading cause of cancer death in American women. In 2017, 252,710 estimate new cases and 40,610 estimate deaths are projected to occur in the United States [1]. Surgery, radiation therapy, systemic treatment and personalized medicine are the main managements for breast cancer. Adjuvant chemotherapy in systemic treatment for breast cancer is popular in China, with about 81.4% of all patients with invasive breast cancer starting chemotherapy [2]. Generally, systemic agents are effective at the beginning of therapy in 90% of primary breast cancers and 50% of metastases. However, drug resistance to therapy is not only common but expected after a variable period of time. To delay the generation of chemoresistance to increase efficacy, chemosensilization is a necessary strategy based on the breast cancer patient with drug-resistant molecular characteristics.

 

Hypoxia microenvironment commonly exists in human solid tumors, including breast cancer, lung cancer, oral cancer and ovarian cancer. It also contributes to the tumor multidrug resistance (MDR) [3]. A growing amount of evidence suggests that drug extrusion by cell membrane pumps, drug-induced apoptosis inhibition and drug target molecules modification might play crucial roles on hypoxia-induced chemotherapeutic resistance [4]. The transcription factor hypoxia-inducible factor-1 (HIF-1) maintained responses to hypoxic environment and closely related to the proliferation, apoptosis, angiogenesis and drug resistance of cancer [5, 6]. One of the most prominent hallmarkers of drug resistance is the over-expression of P-glycoprotein (P-gp). Drug resistance induced by hypoxia mediated by up-regulating P-gp protein expression through HIF-1α activating [7]. Apart from the over-expression of P-gp, apoptosis inhibition is another important mechanism for drug resistance [8]. Since p53, a multi-functional transcription factor that suppresses tumor, could regulate cellular proliferation, cell death, mutagenesis, DNA repair and apoptosis by targeting an array of genes, such as MDM2, BAX, DR4 and DR5 etc [9], hence, p53 activation might overcome drug resistance through inducing apoptosis. It is reported that the hypoxia environment promoted HIF-1α expression and escaped from apoptosis by inhibiting p53 [10].

 

AMP-activated protein kinase (AMPK), the sensor of cellular energy, is activated by hypoxia to compensate the reduced mitochondrial respiration [11, 12]. AMPK modulating P-gp was involved in hypoxia-induced multidrug resistance in human cancer cells [13]. Berberine (Ber), an isoquinoline alkaloid purified from the Berberis species, has exhibited multiple pharmacological activities, including antibacterial, anti-hypertensive, antiarrhythmic and antitumor effect [14]. Moreover, it has been showed that berberine overcomed radio-resistance in colon cancer by inhibiting P-gp expression [15]. Berberine also has been reported to downregulate AMPK expression in ischemic areas of rat heart caused by ligating coronary artery [16]. Therefore, we hypothesized that berberine might overcome drug resistance induced by hypoxia, but its molecular mechanisms still need to further explore.

 

In this study, we firstly set up the drug-resistant cell model using MCF-7 cell under the condition of hypoxia. Secondly, we investigated whether berberine could overcome DOX chemoresistance on MCF-7/hypoxia cell and revealed the relative molecular mechanisms. Thirdly, the transplanted mice model bearing drug-resistant tumor was used to detect whether berberine could resensitilize DOX resistance in vivo. This work is beneficial to attempt a novel strategy for drug-resistance cancer treatment.

Materials and Methods

Chemicals and reagents

 

Sulforhodamine B was purchased from Sigma Aldrich. IOX2 and AICAR were purchased from Selleckchem. DMEM medium, fetal bovine serum (FBS), penicillin, streptomycin and BCA protein assay kits were from Beyotime Institute of Biotechnology (Haimen, China). The primary antibodies were diluted 1:1000 before use, including AMPK (Cat. # sc-25792, Santa Cruz Biotechnologies), p-AMPK (Cat. # sc-33524, Santa Cruz Biotechnologies), HIF-1α (Cat. #113642 Abcam), P-gp (Cat. # sc-55510, Santa Cruz Biotechnologies), p53 (Cat. # 10442-1-AP, Proteintech), Bax (Cat. # sc-7480, Santa Cruz Biotechnologies), Cytochrome c (Cat. # sc-13561, Santa Cruz Biotechnologies), Caspase 9 (Cat. # 842, Cell signaling), Caspase 3 (Cat. # 836, Cell signaling), PARP (Cat. # 1442, Cell signaling) and β-actin (Cat. # sc-130300, Santa Cruz Biotechnologies). All the chemical compounds were analytically pure reagents. Berberine is a gift from Northeast Pharmaceutical Factory. All other chemicals and reagents were of analytical grade.

Cell culture and SRB assay

 

MCF-7 cells were maintained in DMEM high glucose medium supplemented with 10% fetal bovine serum (FBS), 100 units/mL penicillin, and 100 μg/mL streptomycin in an atmosphere of 95% air and 5% CO2 at 37. For hypoxic exposure, MCF-7 cells were maintained in DMEM high glucose medium supplemented with 10% fetal bovine serum (FBS), 100 units/mL penicillin, and 100 μg/mL streptomycin and cultured in a modulator incubator chamber at 37°C with 94% N2, 1% O2 and 5% CO2 for at least 7 days. The sulforhodamine B (SRB) assay is routinely used for cytotoxicity determination. MCF-7 and MCF-7/hypoxia were seeded in 96 well plates at a density of 5×103 cells per well overnight, and treated with the indicated with DOX at final concentrations of 0, 0.04, 0.08, 0.16, 1.25,2.5, 5, 10, 20 and 40 μg/mL for 48 h. MCF-7/hypoxia treated with Berberine at final concentrations of 0, 1.25, 2.5, 5, 10, 20, 40, 80 and 160 μM and/or 0.8 μM AICAR for 48h. MCF-7/hypoxia treated with Berberine at final concentrations of 0, 1.25, 2.5, 5, 10, 20, 40, 80, 160μM and/or 6.25 μM IOX2 for 48 h. MCF-7/hypoxia were seeded at a density of 5×103 cells/well overnight, and treated with DOX at final concentrations of 0, 0.04, 0.08, 0.16, 1.25, 2.5, 5 μg/mL and co-treated with 2.5, 5, 10 μM berberine separately. MCF-7/hypoxia treated with different concentrations DOX and co-treated with 2.5, 5, 10 μM berberine separately were indicated with/or 0.8 μM AICAR for 48h. MCF-7/hypoxia treated with different concentrations DOX and co-treated with 2.5, 5, 10 μM berberine separately were indicated with/or 6.25 μM IOX2 for 48 h. the cells were fixed with 10% trichloroacetic acid, and 0.4% (w/v) SRB in 1% acetic acid was added to stain the cells. Unbound SRB was washed away with 1% acetic acid and SRB-bound cells were rendered soluble with 10 mM Tris-base (pH 10.5; Sigma Aldrich). The absorbance was read at a wavelength of 570 nm.

Apoptosis detection by flow cytometry

 

Cell death and apoptosis were detected with an Annexin V-FITC Apoptotic Detection Kit by flow cytometry. After treating with 0, 5 and 40 μM berberine for 48 h, MCF-7/hypoxia cells were harvested and washed twice with cold PBS. The cell pellets were resuspended with binding buffer to cell suspension at a density of 1×l06 cells/mL. Then 5 μL of FITC-conjugated annexin V was added to the suspension and incubated for 15 min at 4°C in the dark. After that, 5 μL of propidium iodide (PI) was injected into the mixture and incubated with cells for 5 min. The samples were subsequently analyzed by flow cytometry with an FACS Calibur flow cytometer (BD Biosciences, San Jose, CA, USA). The excitation wavelength was 488 nm, the emission of FITC-conjugated annexin V was 515 nm and the propidium iodide (PI) emission was 560 nm.

Western blot

 

MCF-7 and MCF-7/hypoxia cells total protein and cytoplasm were collected. MCF-7/hypoxia were grown in berberine with the final concentrations of 0, 5, 40 μM for 48 h, total protein and cytoplasm were collected. MCF-7/ hypoxia were treated with the final concentrations of 0, 5, 40 μM and/or 0.8 μM AICAR for 48h, total protein was collected. MCF-7/hypoxia were treated with the final concentrations of 0, 5, 40 μM and and/or 6.25 μM IOX2 for 48 h, total protein was collected. Total protein was extracted from tumor tissue or cells were washed with ice-cold PBS and lysed with RIPA Cell Lysis Buffer (Cell Signaling) containing a phosphatase inhibitor and the protease inhibitor cocktail (Sigma) by incubating on ice for 30 min. Lysates were collected by centrifugation and protein concentrations were determined by the BCA method. The samples were separated on 12% SDS-PAGE and transferred onto polyvinylidene fluoride (PVDF) membranes. After blocking in TBS buffer (150 mM NaCl, 10 mM Tris, pH 7.4) containing 5% nonfat milk, the blots were incubated with a primary antibody (rabbit anti AMPK, p-AMPK, HIF-1α, P-gp, p53, Bax, cytochrome c, Caspase 9, Caspase 3, PARP and β-actin) at 4 °C overnight and secondary antibody for 1 h at room temperature. The corresponding horseradish peroxidase-conjugated secondary antibodies (1:2000 dilutions) were incubated at room temperature. The blots were visualized by super ECL and quantified by software Quantity One (BIO-RAD).β-actin was used as the internal control.

Subcutaneous transplanted tumor model in nude mice

 

Animal experiment protocols were approved by the Ethics Committee for the Use of Experimental Animals of Jilin University. MCF-7/hypoxia (2 × 106) were collected in 70 μL PBS and mixed with 70 mL Matrigel Matrix (Becton Dickinson Biosciences). The mixture was injected subcutaneously on one side of the dorsal flank of 8-week-old female BALB/c nu/nu mice (Vital River Laboratories, Beijing, China). When tumor volume reached 60100 mm3, mice were randomized into 5 groups (n=6). The mice in control group treated with saline injected by tail vein every 3 days, the DOX group treated with DOX (1 mg·kg-1) by tail vein injection every 3 days, the low dose berberine(Ber-L) group treated with berberine (5 mg·kg-1) daily by oral gavage, the low dose berberine combined with DOX group (Ber-L+DOX) treated with berberine (5 mg·kg-1) daily by oral gavage and DOX (1 mg·kg-1) by tail vein injection every 3 days, the high dose berberine group treated with berberine (200mg·kg-1) daily by oral gavage. The body weights and tumor sizes were accurately recorded every three days, the tumor volume was calculated according to the formula: length×Width2×0.52. The mice were sacrificed 25 days after drug administration. At the end of the study, the tumor tissues were isolated and stored in -80 °C immediately for later analysis.

Statistical analysis

 

All data were expressed as mean ± SD. Statistical significances among groups were analyzed by one-way analysis of variance (ANOVA) followed by Dunnett's multiple comparison post. A value with p < 0.05 was considered as statistically significant.

Results

Hypoxia increases DOX resistance on breast cancer cells with AMPK activation

 

To investigate the effect of hypoxia on DOX chemotherapy sensitivity, MCF-7 cells in controlled normoxia environment (MCF-7/normoxia) and MCF-7 cells in controlled hypoxia environment (MCF-7/hypoxia) were relatively exposed to the various concentrations of DOX (0.0440 μg/mL) for 48 h. Cell viability was determined by SRB assay. Compared with MCF-7/normoxia, the cell viability in MCF-7/hypoxia increases about 8.4%60.1% at the DOX dosage range from 0.16 μg/mL to 10μg/mL (Fig. 1A), and hypoxia reduced the DOX intracellular concentration (Fig. S1), indicating that hypoxia induces DOX chemoresistance. To discuss the related drug-resistant proteins in MCF-7 cell under hypoxia, we evaluated AMPK signaling pathway, which is correlated with enzyme metabolism under hypoxia. It is showed that the protein expressions of the phosphorylated AMPK (p-AMPK), HIF-1α and P-gp significantly increased, indicating that hypoxia induces the activation of AMPK (Fig. 1B, S2).

Cytotoxicity effect of berberine on MCF-7/hypoxia cells

 

To assess cytotoxicity profile of berberine on MCF-7/hypoxia cells, a series of concentrations of berberine (from 1.25160 µM) were used to treat MCF-7/hypoxia cells for 48 h and 72 h. As shown in Fig. 2A, berberine has negligible influence on cell growth when the concentration is less than 10 µM. However, when the concentration is more than 20 µM, berberine inhibits MCF-7/hypoxia cell growth in a time- and dose-dependent manner, and then apoptosis of MCF-7/hypoxia cell treated with 5 µM and 40 µM berberine for 48 h was determined by flow cytometry, as shown in Fig. 2B, early apoptotic rate (Q4: 3.1±0.53% vs. 2.85±0.95%) and late apoptotic or necrotic rate (Q2: 3.51±0.79 % vs. 3.71±0.83%) in 5 µM berberine have no significant difference compared with control group, but in 40 µM berberine treatment group, the early apoptotic rate is 10.67±1.88%, the late apoptotic or necrotic rate is 28.73±6.21% , indicating that high dose berberine (40 µM) could cause MCF-7/hypoxia cells apoptosis.

 

Moreover, we detected the protein expressions in AMPK signaling pathway and canonical mitochondrial apoptosis pathway. It is showed that a-week-hypoxia induced p-AMPK, HIF-1α and P-gp protein expressions of MCF-7/hypoxia cell in a stable and high level, in contrast to MCF-7/normoxia (Fig. 1B S2). However, berberine decreases the three protein expressions in dose-dependent manner. High-dose berberine significantly activates p53 and mitochondrial apoptosis pathway with a series of proteins releasing, including BAX, Cytochrome c, cleaved-Caspase 9, cleaved-Caspase 3 and cleaved PARP (Fig. 2C, S3). According to this results, we designed using low dose berberine (less than 10 µM) combining with DOX to detect the change of DOX chemosensitivity.

Figure 1

 

Hypoxia reduced the DOX chemoresistance with the AMPK signaling pathway in MCF-7/hypoxia (A) The DOX cytotoxicity effect in MCF-7/normoxia and MCF-7/hypoxia cell. Mean values ± SD, * P <0.05, MCF-7/normoxia vs. MCF-7/hypoxia (B) AMPK, p-AMPK, HIF-1α and P-gp proteins expression in MCF-7/normoxia and MCF-7/hypoxia cell.

Int J Biol Sci Image (Click on the image to enlarge.)

Figure 2

 

The apoptosis effect in MCF-7/hypoxia caused by berberine (A) The cytotoxicity effect in MCF-7/hypoxia cell caused by berberine for 48 and 72h. Mean values ± SD, * P<0.05, cells treated with different concentrations of berbeine for 48 h vs. control group. # P <0.05, cells treated with different concentrations of berberine for 72 h vs. control group. (B) The apoptosis rate in MCF-7/hypoxia caused by 0,5 and 40 μM berberine for 48 h. (C) AMPK, p-AMPK, HIF-1α, P-gp, p53, Bax, cytochrome c, Caspase 9, Caspase 3 and PARP proteins expression by 0,5 and 40 μM berberine treatment for 48 h in MCF-7/hypoxia. Each result was repeated three times.

Int J Biol Sci Image (Click on the image to enlarge.)

Low-dose berberine resensitized DOX chemosensitivity of MCF-7/hypoxia cells

 

To investigate whether low-dose berberine could increase DOX chemosensitivity, we treated MCF-7/hypoxia cells with DOX (concentrations from 0.04 to 5 μg/mL) for 48 h and 72 h combined with low concentrations of berberine (2.5 μM, 5 μM and 10 μM). As shown in Fig. 3A and 3B, low-dose berberine (2.510 μM) significantly improves DOX sensitivity on MCF-7/hypoxia cells for 48 h and 72 h treatment, IC50 of DOX decreases from 2.48 μg/mL (DOX alone) to 1.37 μg/mL (combined with 2.5 μM berberine), 0.49μg/mL (combined with 5 μM berberine) and 0.34 μg/mL (combined with 10 μM berberine) for 48 h treatment. Giving that a 10 μM berberine alone has negligible effect on cell growth of MCF-7/hypoxia cells (Fig. 2A), it indicates that low-dose berberine could resensitize the DOX chemsensitivity to MCF-7/hypoxia cell lines.

Low-dose berberine suppresses P-gp by down-regulating the AMPK-HIF-1α signaling pathway

 

To explore the downstream of AMPK signaling, we used AMPK activator AICAR to find out the downstream target proteins of AMPK. As indicated in Fig. 3A, low-dose berberine (5 μM) combined with DOX strongly inhibits MCF- 7/hypoxia cell growth, however, in the presence of AICAR, the inhibition of cell growth is significantly weaken compared with the same concentration of the berberine plus DOX treatment (Fig. 4A). As shown in Fig. 4C and S4, AICAR up-regulating p-AMPK protein expression, counteracts the inhibition of p-AMPK induced by low-dose berberine. And HIF-1α and P-gp protein expressions increase with p-AMPK up-regulation induced by AICAR, indicating that HIF-1α and P-gp are the downstream of AMPK.

 

To further explore the relationship between HIF-1α and P-gp, HIF-1α stabilizer IOX2 was used. IOX2 can stabilize HIF-1α by selectively inhibiting prolyl-4-hydroxylase-2 (PHD-2), which can covalently modify two proline residues in the oxygen-dependent degradation (ODD) domain of HIF-1α subunits to promote HIF-1α degradation under hypoxia [17,18]. The increase of DOX chemosensitivity induced by berberine in MCF-7/hypoxia cells is weaken by the addition of IOX2 together with up-regulation of P-gp protein expression, and at the same time, the p-AMPK expression do not change (Fig. 5A, 5C and S5). Our result revealed HIF-1α is a downstream protein of the AMPK and regulates the expression of P-gp in MCF-7/hypoxia cells.

 

Moreover, the mitochondrial apoptosis related protein Bax, Cytochrome c, cleaved-Caspase 9, cleaved-Caspase 3 and cleaved-PARP do not changed after 5 μM berberine alone treatment (Fig. 2C and S3), suggesting the mitochondrial apoptosis is not involved in the mechanism of DOX chemosensitivity of low dose berberine. In summary, it is demonstrated that low-dose berberine increases DOX chemosensitivity by inhibiting AMPK, subsequently down-regulation of HIF-1α and P-gp expression.

Figure 3

 

Low-dose berberine resensitized the DOX chemoresistance in MCF-7/hypoxial (A, B) Cell viability of low-dose berberine (2.5, 5 and 10 μM) combined with DOX in MCF-7/hypoxia cells for 48 h and 72 h treatment. Mean values ± SD, * P<0.05, cells treated with different concentrations of DOX vs. control group. # P <0.05, cells treated with different concentrations of DOX combined with 2.5 μM berberine vs. control group. P <0.05, cells treated with different concentrations of DOX combined with 5 μM berberine vs. control group. ¤ P <0.05, cells treated with different concentrations of DOX combined with 10 μM berberine, vs. control group.

Int J Biol Sci Image (Click on the image to enlarge.)

Figure 4

 

The effect of AMPK on berberine sensitized DOX resistance and inhibited cell growth in MCF-7/hypoxia. (A) Cell viability in MCF-7/hypoxia cells after DOX combined with 5 μM berberine treatment, or DOX combined with 5 μM berberine and AICAR treatment for 48 h. Mean values ± SD, * P <0.05, MCF-7/hypoxia cells treated with DOX combined with 5 μM berberine for 48 h vs. MCF-7/hypoxia cells treated with DOX combined with 5 μM berberine and AICAR for 48 h. (B) Cell viability in MCF-7/hypoxia cells after berberine treatment or berberine and AICAR treatment for 48 h. * P <0.05, MCF-7/hypoxia cells treated with different concentrations of berberine for 48 h vs. MCF-7/hypoxia cells treated with different concentrations of berberine and AICAR for 48 h. (C) AMPK, HIF-1α, P-gp and p53 proteins expression after berberine treatment or berberine and AICAR treatment for 48 h in MCF-7/hypoxia cell. Each result was repeated three times.

Int J Biol Sci Image (Click on the image to enlarge.)

Figure 5

 

The effect of HIF-1α on berberine sensitized DOX resistance and inhibited cell growth in MCF-7/hypoxia. (A) Cell viability in MCF-7/hypoxia cells after DOX combined with 5 μM berberine treatment, or DOX combined with 5 μM berberine and IOX2 treatment for 48 h. Mean values ± SD, * P <0.05, MCF-7/hypoxia cells treated with DOX combined with 5 μM berberine for 48 h vs. MCF-7/hypoxia cells treated with DOX combined with 5 μM berberine and IOX2 for 48 h. (B) Cell viability in MCF-7/hypoxia cells after berberine treatment or berberine and IOX2 treatment for 48 h. * P <0.05, MCF-7/hypoxia cells treated with different concentrations of berberine for 48 h vs. MCF-7/hypoxia cells treated with different concentrations of berberine and IOX2 for 48 h. (C) AMPK, HIF-1α, P-gp and p53 proteins expression after berberine treatment or berberine and IOX2 treatment for 48 h in MCF-7/hypoxia cell. Each result was repeated three times.

Int J Biol Sci Image (Click on the image to enlarge.)

High-dose berberine induces apoptosis by AMPK-HIF-1α downregulaton inducing p53 activation

 

It is showed that high-dose berberine (40 μM) could directly induce apoptosis in MCF-7/hypoxia cells (Fig.2B). It is found that high-dose berberine (40 μM) could inhibit AMPK, HIF-1α, P-gp and activate p53 (Fig. 2C and S3). To explore the downstream of AMPK signaling, AMPK activator (AICAR) and HIF-1α stabilizer IOX2 were used. As showed in Fig 4B, cytotoxicity of berberine (more than 40μM) is significantly decreased by AMPK activator AICAR. As shown in Fig. 4C and S4, AICAR up-regulates high-dose berberine-induced AMPK inhibition, and high-dose berberine-induced the inhibition of HIF-1α, P-gp and activation of p53 expression are prevented by AICAR, indicating that HIF-1α,P-gp and p53 are the downstream of AMPK.

 

To further explore the relationship between HIF-1α and p53, HIF-1α stabilizer IOX2 was used. The cytoxicity induced by high-berberine in MCF-7/hypoxia cells is weaken by the addition of IOX2 together with down-regulation of p53 protein expression, and at the same time, the p-AMPK expression does not change (Fig. 5B and 5C, S5). Our result reveals HIF-1α is a downstream protein of the AMPK and regulates the expression of p53 under hypoxia microenvironment in MCF-7 cell. Therefore, high-dose berberine promote apoptosis in drug-resistant breast cancer through AMPK-HIF-1α downregulaton inducing p53 activation.

Berberine overcomes drug resistance in vivo

 

The mice transplanted tumor models were used to evaluate berberine overcoming DOX resistance in hypoxia induced MCF-7 drug resistance breast cancer. Five groups were set up as Con, DOX, low dose berberine (Ber-L), low dose berberine combined with DOX (Ber-L+DOX) and high dose berberine (Ber-H). Fig. 6A-C show that tumor volumes and weights are significantly reduced in the DOX, Ber-L+DOX and Ber-H group comparing with control group, Ber-L alone group has no difference with control group and there has significant difference between Ber-L+DOX with either of Ber-L or DOX alone group, indicating that berberine increases the cytotoxicity of DOX in vivo.

 

Moreover, we detected the relative protein in AMPK signaling pathway in MCF-7/hypoxia xenograft. As shown in Fig. 7 and S6, low-dose berberine significantly induces the inhibition of AMPK and down-regulates the expression of HIF-1α and P-gp, while high-dose berberine promotes the expression of p53 by inhibiting AMPK- HIF-1α signaling pathway, which are consistent with the results in vitro.

Figure 6

 

The overcoming hypoxia induced breast cancer drug resistance effect of berberine in vivo. (A) tumor photographs (B) tumor volume Mean values ± SD, * P<0.05, DOX vs. control group. # P <0.05, Ber-L+DOX vs. control group. P <0.05, Ber-H vs. control group. (C) tumor weight * P<0.05, mice treated with DOX or (and) berberine vs. control group, # P <0.05 Ber-L+DOX vs. DOX or Ber-L.

Int J Biol Sci Image (Click on the image to enlarge.)

Figure 7

 

AMPK, p-AMPK, HIF-1α, P-gp and p53 proteins expression in MCF-7/hypoxia xenograft. Each result was repeated three times.

Int J Biol Sci Image (Click on the image to enlarge.)

Discussion

 

Breast cancer is the most common type of cancer and the second leading cause of cancer death in American women. In 2017, 252,710 estimate new cases and 40,610 estimate deaths are projected to occur in the United States [1]. Surgery, radiation therapy, systemic treatment and personalized medicine are the main managements for breast cancer. Adjuvant chemotherapy in systemic treatment for breast cancer is popular in China, with about 81.4% of all patients with invasive breast cancer starting chemotherapy [2]. Generally, systemic agents are effective at the beginning of therapy in 90% of primary breast cancers and 50% of metastases. However, drug resistance to therapy is not only common but expected after a variable period of time. To delay the generation of chemoresistance to increase efficacy, chemosensitivity is a necessary strategy based on the breast cancer patient with drug-resistant molecular characteristics.

 

DOX is the most frequently used chemotherapy combined with cyclophosphamide or 5-fluorouracil. However, recent researches show that the effectiveness of DOX is considerably limited in a hypoxic microenvironment (pO2 ≤ 2.5 mmHg), which is typically presented in the central region of solid tumors, such as breast cancer, glioblastoma multiforme, cervical cancer, lung adenocarcinoma and hepatocellular carcinoma [19]. Hypoxia-induced MDR is one of major influencing factors on cancer therapy effectiveness [20]. AMPK is the most important cellular energy sensor which is activated by hypoxia to compensate the reduction of mitochondrial respiration. Moreover, It has been reported that AMPK activation under hypoxia induced the drug resistance in osteosarcoma (MG-63) cells [21]. In our study, we used controlled hypoxia condition to culture MCF-7 cells for about one week, the survived MCF-7 cells became hypoxia-stable and expressed higher level of AMPK than its counterpart parents. Berberine treatment enhanced the chemosensitivity of DOX to MCF-7/hypoxia in low dose and induced apoptosis in high dose, which accompanied the down-regulation of AMPK-HIF-1α. AMPK activator (AICAR) and HIF-1α stabilizer (IOX2) increase chemoresistance of DOX and apoptosis tolerance, indicating that AMPK-HIF-1α inactivation is involved in this process. It is previously reported that AMPK inhibited HIF-1α protein expression in colorectal cancer, breast cancer and gallbladder cancer cell lines under the environment of normoxia, and the canonical mechanism related to the inhibition of mTOR in translational level [22, 23]. However, we found that under the hypoxia condition, AMPK activated HIF-1α protein expression after different doses of berberine treatment. We inferred the relative mechanisms from other studies. It is probably because that the activated AMPK under hypoxia promotes the nuclear export of histone deacetylase 5 (HDAC5), which can promote the formation of more mature Hsp90-HIF-1α complex from separating less mature Hsp70-HIF-1α complex by deacetylating Hsp70, subsequently prevents the degradation of HIF-1α [24].

 

In the present study, we found an intriguing fact that the protein expressions of AMPK and HIF-1α were down-regulated by berberine, both low dose and high dose. But the downstream of HIF-1α occurred the bifurcation dependent on the dosage of berberine: HIF-1α-P-gp inactivation played a crucial role on the DOX chemosensitivity of low-dose berberine, while HIF-1α down-regulation inducing p53 activation led to apoptosis in high-dose berberine. HIF-1α is the oxygen sensor which is significantly activated in response to hypoxia [25]. Over-expressed HIF-1α is closely related chemoresistance by activating P-gp [20, 26, 27]. Consistence to these reports, our results showed that low-dose berberine could enhance DOX cheomsensitivity by inhibiting HIF-1α and P-gp expression in MCF-7/hypoxia cells. When treated with IOX2, a HIF-1α stabilizer, DOX cheomsensitivity enhanced by berberine was weaken together with the up-regulation of P-gp expression. p53 absence is associated with an increased risk of drug resistance development [28]. Our results showed high-dose berberine induced apoptosis by inhibiting HIF-1α expression and up-regulating downstream p53. IOX2 reduced the apoptosis and p53 expression after high dose berberine treatment in MCF-7/hypoxia cells. These indicated that HIF-1α plays the bridging role between AMPK and p53 in high-dose berberine-induced apoptosis under hypoxia.

 

In summary, this work showed that low-dose berberine could enhance DOX chemosensitivity on hypoxia-induced drug-resistant in vivo and in vitro through the AMPK-HIF-1α-P-gp pathway. High-dose berberine directly induced apoptosis on drug-resistantt breast cancer by AMPK-HIF-1α-p53 pathway. Our observations shed light on a potentially therapeutic attempt to overcome drug-resistant breast cancer.

Supplementary Material

Attachment

 

Supplementary figures.

Acknowledgements

 

Prof. Fengying Guan, Wenliang Liu, Fan Yao and Yang Yu are acknowledged for their help in preparing the paper. This work is sponsored by National Natural Science Foundation of China (81201804, 81371681), and the Opening Project of State Key Laboratory of Supramolecular Structure and Materials of Jilin University under Grant No. SKLSSM 201504 and 201713. Undergraduate innovative program of Jilin University (2016B79690, 2016A79311). Most of experiments were carried out at Nanomedicine Engineering Laboratory of Jilin Province and Preclinical Pharmacology R&D Center of Jilin Province.

Competing Interests

 

The authors have declared that no competing interest exists.

  1. The Warburg effect in tumor progression: mitochondrial oxidative metabolism as an anti-metastasis mechanism. 

 

  1. Overcoming cisplatin resistance of ovarian cancer cells by targeting HIF-1-regulated cancer metabolism. Cancer Lett. 2016
  2.  Ursolic acid sensitized colon cancer cells to chemotherapy under hypoxia by inhibiting
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