Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Cancer Cell International
Published in: Cancer Cell International 1/2017

Open Access 01-12-2017 | Primary Research

Curcumin reduces mitomycin C resistance in breast cancer stem cells by regulating Bcl-2 family-mediated apoptosis

Authors: Qian-Mei Zhou, Yang Sun, Yi-Yu Lu, Hui Zhang, Qi-Long Chen, Shi-Bing Su

Published in: Cancer Cell International | Issue 1/2017

Login to get access

Abstract

Background

Curcumin, a natural compound derived from the turmeric rhizome Curcuma longa Linn, has anticancer and chemoresistance reduction biological activities. We evaluated the efficacy of curcumin in sensitizing chemotherapy drugs through regulation of Bcl-2-mediated apoptosis in breast cancer stem-like cells (BCSCs).

Methods

Cell survival was measured using MTT assay. Apoptosis-related proteins were observed using western blot analysis. Apoptosis was detected with flow cytometric analysis and by Hoechst 33258 staining. The mitochondrial membrane potential was observed with flow cytometric analysis.

Results

The ability of BCSCs to propagate decreased gradually along the passages and was completely lost at the fifth passage [0.1 μmol/L mitomycin C (MMC) with 5 μmol/L curcumin in MCF-7 and 0.5 μmol/L MMC with 5 μmol/L curcumin in MDA-MB-231 cells]. Curcumin combined with MMC treatment significantly decreased the levels of antiapoptotic Bcl-2 and Bcl-w expression, increased the levels of proapoptotic Bax, Bak, Bad, Bik, and Bim expression, and activated caspase-3 and caspase-9 in MCF-7 BCSCs. In the presence of Bcl-2 siRNA, the apoptosis rate increased by 15% in cells treated with curcumin and MMC. The mitochondrial membrane potential decreased by approximately 20% in MCF-7 BCSCs undergoing the combination treatment of curcumin and MMC. The combination-induced decrease in Bcl-2 was regulated by the presence of the Wnt-specific inhibitor PFK115-584 and PI3k inhibitor LY294002.

Conclusions

Our study indicates that curcumin might represent a novel therapeutic agent for treating breast cancer chemoresistance induced by MMC.
Literature
1.
Fontein DB, de Glas NA, Duijm M, Bastiaannet E, Portielje JE, Van de Velde CJ, et al. Age and the effect of physical activity on breast cancer survival: a systematic review. Cancer Treat Rev. 2013;39:958–65.CrossRefPubMed
2.
Lesiuk T. The effect of mindfulness-based music therapy on attention and mood in women receiving adjuvant chemotherapy for breast cancer: a pilot study. Oncol Nurs Forum. 2015;42:276–82.CrossRefPubMed
3.
Pinto CA, Widodo E, Waltham M, Thompson EW. Breast cancer stem cells and epithelial mesenchymal plasticity—implications for chemoresistance. Cancer Lett. 2013;341:56–62.CrossRefPubMed
4.
Castilla C, Congregado B, Chinchon D, Torrubia FJ, Japon MA, Saez C. Bcl-xL is overexpressed in hormone-resistant prostate cancer and promotes survival of LNCaP cells via interaction with proapoptotic Bak. Endocrinology. 2016;147:4960–7.CrossRef
5.
Williams J, Lucas PC, Griffith KA, Choi M, Fogoros S, Hu YY, et al. Expression of Bcl-xL in ovarian carcinoma is associated with chemoresistance and recurrent disease. Gynecol Oncol. 2005;96:287–95.CrossRefPubMed
6.
Buchholz TA, Davis DW, McConkey DJ, Symmans WF, Valero V, Jhingran A, et al. Chemotherapy-induced apoptosis and Bcl-2 levels correlate with breast cancer response to chemotherapy. Cancer J. 2003;9:33–41.CrossRefPubMed
7.
Yu B, Sun X, Shen HY, Gao F, Fan YM, Sun ZJ. Expression of the apoptosis-related genes BCL-2 and BAD in human breast carcinoma and their associated relationship with chemosensitivity. J Exp Clin Cancer Res. 2010;29:107.CrossRefPubMedPubMedCentral
8.
Chun E, Lee KY. Bcl-2 and Bcl-xL are important for the induction of paclitaxel resistance in human hepatocellular carcinoma cells. Biochem Biophys Res Commun. 2004;315:771–9.CrossRefPubMed
9.
Wong FY, Liem N, Xie C, Yan FL, Wong WC, Wang L, et al. Combination therapy with gossypol reveals synergism against gemcitabine resistance in cancer cells with high BCL-2 expression. PLoS ONE. 2010;7:e50786.CrossRef
10.
Begum-Haque S, Haque A, Kasper LH. Apoptosis in Toxoplasma gondii activated T cells: the role of IFNgamma in enhanced alteration of Bcl-2 expression and mitochondrial membrane potential. Microb Pathog. 2009;47:281–8.CrossRefPubMedPubMedCentral
11.
Berghauser PL, Spoor JK, Venkatesan S, Swagemakers S, Kloezeman JJ, Dirven CM, et al. The Bcl-2 inhibitor Obatoclax overcomes resistance to histone deacetylase inhibitors SAHA and LBH589 as radiosensitizers in patient-derived glioblastoma stem-like cells. Genes Cancer. 2014;5:445–59.
12.
Wu DW, Huang CC, Chang SW, Chen TH, Lee H. Bcl-2 stabilization by paxillin confers 5-fluorouracil resistance in colorectal cancer. Cell Death Differ. 2015;22:779–89.CrossRefPubMed
13.
Nishioka T, Luo LY, Shen L, He H, Mariyannis A, Dai W, et al. Nicotine increases the resistance of lung cancer cells to cisplatin through enhancing Bcl-2 stability. Br J Cancer. 2014;110:1785–92.CrossRefPubMedPubMedCentral
14.
Zhou QM, Zhang H, Lu YY, Wang XF, Su SB. Curcumin reduced the side effects of mitomycin C by inhibiting GRP58-mediated DNA cross-linking in MCF-7 breast cancer xenografts. Cancer Sci. 2009;100:2040–5.CrossRefPubMed
15.
Zhou QM, Wang XF, Liu XJ, Zhang H, Lu YY, Huang S, et al. Curcumin improves MMC-based chemotherapy by simultaneously sensitising cancer cells to MMC and reducing MMC-associated side-effects. Eur J Cancer. 2011;47:2240–7.CrossRefPubMed
16.
Zhou QM, Wang XF, Liu XJ, Zhang H, Lu YY, Su SB. Curcumin enhanced antiproliferative effect of mitomycin C in human breast cancer MCF-7 cells in vitro and in vivo. Acta Pharmacol Sin. 2011;32:1402–10.CrossRefPubMedPubMedCentral
17.
Li Y, Zhang S, Geng JX, Hu XY. Curcumin inhibits human non-small cell lung cancer A549 cell proliferation through regulation of Bcl-2/Bax and cytochrome C. Asian Pac J Cancer Prev. 2013;14:4599–602.CrossRefPubMed
18.
Chiu TL, Su CC. Curcumin inhibits proliferation and migration by increasing the Bax to Bcl-2 ratio and decreasing NF-kappaBp65 expression in breast cancer MDA-MB-231 cells. Int J Mol Med. 2009;23:469–75.PubMed
19.
Chanvorachote P, Pongrakhananon V, Wannachaiyasit S, Luanpitpong S, Rojanasakul Y, Nimmannit U. Curcumin sensitizes lung cancer cells to cisplatin-induced apoptosis through superoxide anion-mediated Bcl-2 degradation. Cancer Investig. 2009;27:624–35.CrossRef
20.
Shankar S, Srivastava RK. Involvement of Bcl-2 family members, phosphatidylinositol 3′-kinase/AKT and mitochondrial p53 in curcumin (diferulolylmethane)-induced apoptosis in prostate cancer. Int J Oncol. 2007;30:905–18.PubMed
21.
Gou Q, Liu L, Wang C, Wu Q, Sun L, Yang X, et al. Polymeric nanoassemblies entrapping curcumin overcome multidrug resistance in ovarian cancer. Colloids Surf B Biointerfaces. 2015;126:26–34.CrossRefPubMed
22.
Roy M, Mukherjee S. Reversal of resistance towards cisplatin by curcumin in cervical cancer cells. Asian Pac J Cancer Prev. 2014;15:1403–10.CrossRefPubMed
23.
Vazquez-Martin A, Oliveras-Ferraros C, Del BS, Martin-Castillo B, et al. The anti-diabetic drug metformin suppresses self-renewal and proliferation of trastuzumab-resistant tumor-initiating breast cancer stem cells. Breast Cancer Res Treat. 2011;126:355–64.CrossRefPubMed
24.
25.
26.
Campbell FC, Collett GP. Chemopreventive properties of curcumin. Futur Oncol. 2005;1:405–14.CrossRef
27.
Lu WD, Qin Y, Yang C, Li L, Fu ZX. Effect of curcumin on human colon cancer multidrug resistance in vitro and in vivo. Clin (Sao Paulo). 2013;68:694–701.CrossRef
28.
Verwey J, de Vries J, Pinedo HM. Mitomycin C-induced renal toxicity, a dose-dependent side effect? Eur J Cancer Clin Oncol. 1987;23:195–9.CrossRefPubMed
29.
Choudhuri T, Pal S, Agwarwal ML, Das T, Sa G. Curcumin induces apoptosis in human breast cancer cells through p53-dependent Bax induction. FEBS Lett. 2002;512:334–40.CrossRefPubMed
30.
Kunnumakkara AB, Anand P, Aggarwal BB. Curcumin inhibits proliferation, invasion, angiogenesis and metastasis of different cancers through interaction with multiple cell signaling proteins. Cancer Lett. 2008;269:199–225.CrossRefPubMed
31.
Revalde JL, Li Y, Hawkins BC, Rosengren RJ, Paxton JW. Heterocyclic cyclohexanone monocarbonyl analogs of curcumin can inhibit the activity of ATP-binding cassette transporters in cancer multidrug resistance. Biochem Pharmacol. 2015;93:305–17.CrossRefPubMed
32.
Rashmi R, Kumar S, Karunagaran D. Ectopic expression of Hsp70 confers resistance and silencing its expression sensitizes human colon cancer cells to curcumin-induced apoptosis. Carcinogenesis. 2004;25:179–87.CrossRefPubMed
33.
Li Y, Revalde JL, Reid G, Paxton JW. Modulatory effects of curcumin on multi-drug resistance-associated protein 5 in pancreatic cancer cells. Cancer Chemother Pharmacol. 2011;68:603–10.CrossRefPubMed
34.
Banerjee A, Qian P, Wu ZS, Ren X, Steiner M, Bougen NM, et al. Artemin stimulates radio- and chemo-resistance by promoting TWIST1-BCL-2-dependent cancer stem cell-like behavior in mammary carcinoma cells. J Biol Chem. 2012;287:42502–15.CrossRefPubMedPubMedCentral
35.
Piche A, Grim J, Rancourt C, Gomez-Navarro J, Reed JC, Curiel DT. Modulation of Bcl-2 protein levels by an intracellular anti-Bcl-2 single-chain antibody increases drug-induced cytotoxicity in the breast cancer cell line MCF-7. Cancer Res. 1998;58:2134–40.PubMed
36.
Fulda S, Debatin KM. Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy. Oncogene. 2006;25:4798–811.CrossRefPubMed
37.
38.
Jaruga E, Salvioli S, Dobrucki J, Chrul S, Bandorowicz-Pikula J, Sikora E. Apoptosis-like, reversible changes in plasma membrane asymmetry and permeability, and transient modifications in mitochondrial membrane potential induced by curcumin in rat thymocytes. FEBS Lett. 1998;433:287–93.CrossRefPubMed
39.
Li Y, Wang P, Chen X, Hu J, Liu Y, Wang X, Liu Q. Activation of microbubbles by low-intensity pulsed ultrasound enhances the cytotoxicity of curcumin involving apoptosis induction and cell motility inhibition in human breast cancer MDA-MB-231 cells. Ultrason Sonochem. 2016;33:26–36.CrossRefPubMed
40.
Fan H, Liang Y, Jiang B, Li X, Xun H, Sun J, He W, Lau HT, Ma X. Curcumin inhibits intracellular fatty acid synthase and induces apoptosis in human breast cancer MDA-MB-231 cells. Oncol Rep. 2016;35(5):2651–6.CrossRefPubMed
41.
Singh DV, Agarwal S, Singh P, Godbole MM, Misra K. Curcumin conjugates induce apoptosis via a mitochondrion dependent pathway in MCF-7 and MDA-MB-231 cell lines. Asian Pac J Cancer Prev. 2013;14(10):5797–804.CrossRefPubMed
42.
Nusse R, Fuerer C, Ching W, Harnish K, Logan C, Zeng A, et al. Wnt signaling and stem cell control. Cold Spring Harb Symp Quant Biol. 2008;73:59–66.CrossRefPubMed
43.
44.
Wang Z, Ma LJ, Kang Y, Li X, Zhang XJ. Dickkopf-3 (Dkk3) induces apoptosis in cisplatin-resistant lung adenocarcinoma cells via the Wnt/beta-catenin pathway. Oncol Rep. 2015;33:1097–106.CrossRefPubMed
45.
Feng W, Yang CX, Zhang L, Fang Y, Yan M. Curcumin promotes the apoptosis of human endometrial carcinoma cells by downregulating the expression of androgen receptor through Wnt signal pathway. Eur J Gynaecol Oncol. 2014;35:718–23.PubMed
46.
Singh BN, Kumar D, Shankar S, Srivastava RK. Rottlerin induces autophagy which leads to apoptotic cell death through inhibition of PI3K/Akt/mTOR pathway in human pancreatic cancer stem cells. Biochem Pharmacol. 2012;84:1154–63.CrossRefPubMed
47.
48.
49.
Xia P, Xu XY. PI3K/Akt/mTOR signaling pathway in cancer stem cells: from basic research to clinical application. Am J Cancer Res. 2015;5:1602–9.PubMedPubMedCentral
50.
Tetsu O, McCormick F. Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature. 1999;398:422–6.CrossRefPubMed
51.
52.
O’Brien CA, Nakashima T, Takayanagi H. Osteocyte control of osteoclastogenesis. Bone. 2013;54:258–63.CrossRefPubMed
Metadata
Title
Curcumin reduces mitomycin C resistance in breast cancer stem cells by regulating Bcl-2 family-mediated apoptosis
Authors
Qian-Mei Zhou
Yang Sun
Yi-Yu Lu
Hui Zhang
Qi-Long Chen
Shi-Bing Su
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2017
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-017-0453-3

Other articles of this Issue 1/2017

Cancer Cell International 1/2017 Go to the issue

Primary Research

miR-1296-5p decreases ERBB2 expression to inhibit the cell proliferation in ERBB2-positive breast cancer

Primary Research

Synergistic anticancer effect of combined crocetin and cisplatin on KYSE-150 cells via p53/p21 pathway

Primary research

miR-335 negatively regulates osteosarcoma stem cell-like properties by targeting POU5F1

Review

An overview of the role of platelets in angiogenesis, apoptosis and autophagy in chronic myeloid leukaemia

Primary Research

Suppression of endothelial cell migration by tumor associated macrophage-derived exosomes is reversed by epithelial ovarian cancer exosomal lncRNA

Primary Research

Overexpression of lncRNA HOXA11-AS promotes cell epithelial–mesenchymal transition by repressing miR-200b in non-small cell lung cancer
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits