Curcumin inhibits proliferation and promotes apoptosis of breast cancer cells

Hu,Shan; Xu,Yingchun; Meng,Liwei; Huang,Liming; Sun,He

doi:10.3892/etm.2018.6345

Curcumin inhibits proliferation and promotes apoptosis of breast cancer cells

Authors:
- Shan Hu
- Yingchun Xu
- Liwei Meng
- Liming Huang
- He Sun
View Affiliations

Affiliations: Department of Breast and Thyroid Surgery, Shaoxing People's Hospital, Shaoxing Hospital of Zhejiang University, Shaoxing, Zhejiang 312000, P.R. China, Clinical Laboratory Center, Shaoxing People's Hospital, Shaoxing Hospital of Zhejiang University, Shaoxing, Zhejiang 312000, P.R. China
Published online on: June 22, 2018 https://doi.org/10.3892/etm.2018.6345
Pages: 1266-1272
Copyright: © Hu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Curcumin is a natural compound that appears to be promising for clinical application, as it has been shown in in vitro and in vivo studies to exert antitumor effects by modulating multiple signaling cellular pathways. In the present study, the antitumor effects of curcumin and its mechanism of action were investigated in cultured breast cancer cells. The MTT assay was used to determine the effect of curcumin on breast cancer cell proliferation, flow cytometry was used to detect alterations of the cell cycle, and western blot analysis was used to determine the expression of signaling molecules involved in the cell cycle, proliferation and apoptosis. The results revealed that curcumin significantly inhibited the proliferation of various breast cancer cell lines, such as T47D, MCF7, MDA‑MB‑231 and MDA‑MB‑468, with an IC50 at the micromolar level, indicating the potent antitumor activity of curcumin. In‑depth study of its mechanism of action revealed that curcumin induced cell cycle arrest at the G2/M phase and decreased the expression of the CDC25 and CDC2 proteins, while increasing the expression of P21. In addition, curcumin inhibited the phosphorylation of protein kinase B (Akt)/mammalian target of rapamycin (mTOR), decreased B‑cell lymphoma 2 (BCL2) and promoted BCL‑2‑associated X protein (BAX) and cleavage of caspase 3, subsequently inducing apoptosis of breast cancer cells. In conclusion, curcumin inhibited the proliferation of breast cancer cells and induced G2/M phase cell cycle arrest and apoptosis, which may be associated with the decrease of CDC25 and CDC2 and increase of P21 protein levels, as well as inhibition of the phosphorylation of Akt/mTOR and induction of the mitochondrial apoptotic pathway. The findings of the present study may provide a basis for the further study of curcumin in the treatment of breast cancer.

View Figures

View References

1	DeSantis CE, Ma J, Sauer Goding A, Newman LA and Jemal A: Breast cancer statistics, 2017, racial disparity in mortality by state. CA Cancer J Clin. 67:439–448. 2017. View Article : Google Scholar : PubMed/NCBI
2	Karimi Z, Jessri M, Houshiar-Rad A, Mirzaei HR and Rashidkhani B: Dietary patterns and breast cancer risk among women. Public Health Nutr. 17:1098–1106. 2014. View Article : Google Scholar : PubMed/NCBI
3	Hart CD, Migliaccio I, Malorni L, Guarducci C, Biganzoli L and Di Leo A: Challenges in the management of advanced, ER-positive, HER2-negative breast cancer. Nat Rev Clin Oncol. 12:541–552. 2015. View Article : Google Scholar : PubMed/NCBI
4	Arnedos M, Vicier C, Loi S, Lefebvre C, Michiels S, Bonnefoi H and Andre F: Precision medicine for metastatic breast cancer-limitations and solutions. Nat Rev Clin Oncol. 12:693–704. 2015. View Article : Google Scholar : PubMed/NCBI
5	Zhou QM, Wang XF, Liu XJ, Zhang H, Lu YY, Huang S and Su SB: Curcumin improves MMC-based chemotherapy by simultaneously sensitising cancer cells to MMC and reducing MMC-associated side-effects. Eur J Cancer. 47:2240–2247. 2011. View Article : Google Scholar : PubMed/NCBI
6	Nagaraju GP, Aliya S, Zafar SF, Basha R, Diaz R and El-Rayes BF: The impact of curcumin on breast cancer. Integr Biol (Camb). 4:996–1007. 2012. View Article : Google Scholar : PubMed/NCBI
7	Quispe-Soto ET and Calaf GM: Effect of curcumin and paclitaxel on breast carcinogenesis. Int J Oncol. 49:2569–2577. 2016. View Article : Google Scholar : PubMed/NCBI
8	Lee JY, Lee YM, Chang GC, Yu SL, Hsieh WY, Chen JJ, Chen HW and Yang PC: Curcumin induces EGFR degradation in lung adenocarcinoma and modulates p38 activation in intestine: The versatile adjuvant for gefitinib therapy. PLoS One. 6:e237562011. View Article : Google Scholar : PubMed/NCBI
9	Yoshida K, Toden S, Ravindranathan P, Han H and Goel A: Curcumin sensitizes pancreatic cancer cells to gemcitabine by attenuating PRC2 subunit EZH2, and the lncRNA PVT1 expression. Carcinogenesis. 38:1036–1046. 2017. View Article : Google Scholar : PubMed/NCBI
10	Gallardo M and Calaf GM: Curcumin inhibits invasive capabilities through epithelial mesenchymal transition in breast cancer cell lines. Int J Oncol. 49:1019–1027. 2016. View Article : Google Scholar : PubMed/NCBI
11	Gallardo M and Calaf GM: Curcumin and epithelial-mesenchymal transition in breast cancer cells transformed by low doses of radiation and estrogen. Int J Oncol. 48:2534–2542. 2016. View Article : Google Scholar : PubMed/NCBI
12	Khalil OAK, de Faria Oliveir OMM, Vellosa JCR, Quadros AU, Dalposso LM, Karam TK, Mainardes RM and Khalil NM: Curcumin antifungal and antioxidant activities are increased in the presence of ascorbic acid. Food Chem. 133:1001–1005. 2012. View Article : Google Scholar
13	Perrone D, Ardito F, Giannatempo G, Dioguardi M, Troiano G, Lo Russo L, Lillo DE A, Laino L and Lo Muzio L: Biological and therapeutic activities, and anticancer properties of curcumin. Exp Ther Med. 10:1615–1623. 2015. View Article : Google Scholar : PubMed/NCBI
14	El-Houseini ME, El-Agoza IA, Sakr MM and El-Malky GM: NNovel protective role of curcumin and taurine combination against experimental hepatocarcinogenesis. Exp Ther Med. 13:29–36. 2017. View Article : Google Scholar : PubMed/NCBI
15	Park MJ, Kim EH, Park IC, Lee HC, Woo SH, Lee JY, Hong YJ, Rhee CH, Choi SH, Shim BS, et al: Curcumin inhibits cell cycle progression of immortalized human umbilical vein endothelial (ECV304) cells by up-regulating cyclin-dependent kinase inhibitor, p21WAF1/CIP1, p27KIP1 and p53. Int J Oncol. 21:379–383. 2002.PubMed/NCBI
16	Kunnumakkara AB, Guha S, Krishnan S, Diagaradjane P, Gelovani J and Aggarwal BB: Curcumin potentiates antitumor activity of gemcitabine in an orthotopic model of pancreatic cancer through suppression of proliferation, angiogenesis, and inhibition of nuclear factor-kappaB-regulated gene products. Cancer Res. 67:3853–3861. 2007. View Article : Google Scholar : PubMed/NCBI
17	Hussain AR, Al-Rasheed M, Manogaran PS, Al-Hussein KA, Platanias LC, Al Kuraya K and Uddin S: Curcumin induces apoptosis via inhibition of PI3′-kinase/AKT pathway in acute T cell leukemias. Apoptosis. 11:245–254. 2006. View Article : Google Scholar : PubMed/NCBI
18	Park C, Kim GY, Kim GD, Choi BT, Park YM and Choi YH: Induction of G2/M arrest and inhibition of cyclooxygenase-2 activity by curcumin in human bladder cancer T24 cells. Oncol Rep. 15:1225–1231. 2006.PubMed/NCBI
19	Yang SX, Polley E and Lipkowitz S: New insights on PI3K/AKT pathway alterations and clinical outcomes in breast cancer. Cancer Treat Rev. 45:87–96. 2016. View Article : Google Scholar : PubMed/NCBI
20	Abraham J: PI3K/AKT/mTOR pathway inhibitors: The ideal combination partners for breast cancer therapies? Expert Rev Anticancer Ther. 15:51–68. 2015. View Article : Google Scholar : PubMed/NCBI
21	Steelman LS, Martelli AM, Cocco L, Libra M, Nicoletti F, Abrams SL and McCubrey JA: The therapeutic potential of mTOR inhibitors in breast cancer. Br J Clin Pharmacol. 82:1189–1212. 2016. View Article : Google Scholar : PubMed/NCBI
22	Donia M, Mangano K, Amoroso A, Mazzarino MC, Imbesi R, Castrogiovanni P, Coco M, Meroni P and Nicoletti F: Treatment with rapamycin ameliorates clinical and histological signs of protracted relapsing experimental allergic encephalomyelitis in Dark Agouti rats and induces expansion of peripheral CD4+CD25+Foxp3+ regulatory T cells. J Autoimmun. 33:135–140. 2009. View Article : Google Scholar : PubMed/NCBI
23	Oaks Z, Winans T, Huang N, Banki K and Perl A: Activation of the mechanistic target of rapamycin in SLE: Explosion of evidence in the last five years. Curr Rheumatol Rep. 18:732016. View Article : Google Scholar : PubMed/NCBI
24	Nicoletti F, Fagone P, Meroni P, McCubrey J and Bendtzen K: mTOR as a multifunctional therapeutic target in HIV infection. Drug Discov Today. 16:715–721. 2011. View Article : Google Scholar : PubMed/NCBI
25	Donia M, McCubrey JA, Bendtzen K and Nicoletti F: Potential use of rapamycin in HIV infection. Br J Clin Pharmacol. 70:784–793. 2010. View Article : Google Scholar : PubMed/NCBI
26	Nicoletti F, Lapenta C, Donati S, Spada M, Ranazzi A, Cacopardo B, Mangano K, Belardelli F, Perno C and Aquaro S: Inhibition of human immunodeficiency virus (HIV-1) infection in human peripheral blood leucocytes-SCID reconstituted mice by rapamycin. Clin Exp Immunol. 155:28–34. 2009. View Article : Google Scholar : PubMed/NCBI
27	Rajamanickam V, Zhu H, Feng C, Chen X, Zheng H, Xu X, Zhang Q, Zou P, He G, Dai X, et al: Novel allylated monocarbonyl analogs of curcumin induce mitotic arrest and apoptosis by reactive oxygen species-mediated endoplasmic reticulum stress and inhibition of STAT3. Oncotarget. 8:101112–101129. 2017. View Article : Google Scholar : PubMed/NCBI
28	Deck LM, Hunsaker LA, Vander Jagt TA, Whalen LJ, Royer RE and Vander Jagt DL: Activation of anti-oxidant Nrf2 signaling by enone analogues of curcumin. Eur J Med Chem. 143:854–865. 2018. View Article : Google Scholar : PubMed/NCBI
29	Chen S, Nimick M, Cridge AG, Hawkins BC and Rosengren RJ: Anticancer potential of novel curcumin analogs towards castrate-resistant prostate cancer. Int J Oncol. 52:579–588. 2018.PubMed/NCBI
30	Pan Y, Liu G, Xiao J, Su B, Zhou F and Wei Y: A novel curcuminoid exhibits enhanced antitumor activity in nasopharyngeal carcinoma. Int J Oncol. 48:2175–2183. 2016. View Article : Google Scholar : PubMed/NCBI
31	Chang LC, Hsieh MT, Yang JS, Lu CC, Tsai FJ, Tsao JW, Chiu YJ, Kuo SC and Lee KH: Effect of bis(hydroxymethyl) alkanoate curcuminoid derivative MTH-3 on cell cycle arrest, apoptotic and autophagic pathway in triple-negative breast adenocarcinoma MDA-MB-231 cells: An in vitro study. Int J Oncol. 52:67–76. 2018.PubMed/NCBI
32	Taurin S, Nimick M, Larsen L and Rosengren RJ: A novel curcumin derivative increases the cytotoxicity of raloxifene in estrogen receptor-negative breast cancer cell lines. Int J Oncol. 48:385–398. 2016. View Article : Google Scholar : PubMed/NCBI