Co-administration of apigenin with doxorubicin enhances anti-migration and antiproliferative effects via PI3K/PTEN/AKT pathway in prostate cancer cells
DOI:
https://doi.org/10.32471/exp-oncology.2312-8852.vol-43-no-2.16096Keywords:
apigenin, cell migration, doxorubicin, PC3, prostate cancerAbstract
Summary. Prostate cancer is one of the leading cancers in men, and new approaches are needed for its treatment. The aim of this study was to investigate the effect of co-administration of naturally occurring flavone apigenin and doxorubicin to androgen-insensitive prostate cancer cells. Methods: The effect of the treatment on survival and migration of human PC3 cells was evaluated by MTT and scratch assay, respectively. Apoptosis and cell cycle distribution were detected by image-based cytometry. mRNA and protein expression were determined by real-time quantitative polymerase chain reaction and Western blot, respectively. Results: Apigenin and doxorubicin dose-dependently inhibited cell survival, and co-administration of both agents significantly induced cell death via upregulating the mRNA expression of caspases, Bax and cytochrome c, and downregulating Bcl-XL. Combination therapy caused cell cycle arrest by upregulating the expression of p21 and p27. The treatment modality inhibited cell migration via downregulating Snail, Twist and MMPs in which doxorubicin was ineffective. Apigenin dephosphorylated Akt strongly, significantly suppressed ERK phosphorylation, and increased PTEN expression 4.5-fold. The combination of apigenin and doxorubicin inhibited PI3K and AKT phosphorylation more strongly than a single administration. Conclusions: Our data indicate that a combination of the natural flavone apigenin with doxorubicin might have a potential in treatment of castration-resistant prostate cancer.
References
Li Y, Huang Q, Zhou Y, et al. The clinicopathologic and prognostic significance of programmed cell death ligand 1 (PD-L1) expression in patients with prostate cancer: a systematic review and meta-analysis. Front Pharmacol 2018; 9: 1494.
Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68: 394–424.
Green SM, Mostaghel EA, Nelson PS. Androgen action and metabolism in prostate cancer. Mol Cell Endocrinol 2012; 360: 3–13.
Gamat M, McNeel DG. Androgen deprivation and immunotherapy for the treatment of prostate cancer. Endocr Relat Cancer 2017; 24: T297–310.
Omlin A, Sartor O, Rothermundt C, et al. Analysis of side effect profile of alopecia, nail changes, peripheral neuropathy, and dysgeusia in prostate cancer patients treated with docetaxel and cabazitaxel. Clin Genitourin Cancer 2015; 13: e205–8.
Singer EA, Srinivasan R. Intravenous therapies for castration-resistant prostate cancer: toxicities and adverse events. Urol Oncol 2012; 30: S15–9.
Chen J, Chen B, Zou Z, et al. Costunolide enhances doxorubicin-induced apoptosis in prostate cancer cells via activated mitogen-activated protein kinases and generation of reactive oxygen species. Oncotarget 2017; 8: 107701–15.
Goodin S, Rao KV, DiPaola RS. State-of-the-art treatment of metastatic hormone-refractory prostate cancer. Oncologist 2002; 7: 360–70.
Putri H, Jenie RI, Handayani S, et al. Combination of potassium pentagamavunon-0 and doxorubicin induces apoptosis and cell cycle arrest and inhibits metastasis in breast cancer cells. Asian Pac J Cancer Prev 2016; 17: 2683–8.
Yang MC, Lin RW, Huang SB, et al. Bim directly antagonizes Bcl-xl in doxorubicin-induced prostate cancer cell apoptosis independently of p53. Cell Cycle 2016; 15: 394–402.
Shabalala S, Muller CJF, Louw J, Johnson R. Polyphenols, autophagy and doxorubicin-induced cardiotoxicity. Life Sci 2017; 180: 160–70.
Wang M, Firrman J, Liu L, Yam K. A Review on flavonoid apigenin: dietary intake, adme, antimicrobial effects, and interactions with human gut microbiota. Biomed Res Int 2019; 2019: 7010467.
Kumar S, Pandey AK. Chemistry and biological activities of flavonoids: an overview. Sci World J 2013; 2013: 162750.
Erdogan S, Doganlar O, Doganlar ZB, et al. The flavonoid apigenin reduces prostate cancer CD44(+) stem cell survival and migration through PI3K/Akt/NF-kappaB signaling. Life Sci 2016; 162: 77–86.
Gao AM, Zhang XY, Ke ZP. Apigenin sensitizes BEL-7402/ADM cells to doxorubicin through inhibiting miR-101/Nrf2 pathway. Oncotarget 2017; 8: 82085–91.
Zhao T, He Y, Chen H, et al. Novel apigenin-loaded sodium hyaluronate nano-assemblies for targeting tumor cells. Carbohydr Polym 2017; 177: 415–23.
Sung B, Chung HY, Kim ND. Role of Apigenin in cancer prevention via the induction of apoptosis and autophagy. J Cancer Prev 2016; 21: 216–26.
Shukla S, Gupta S. Molecular mechanisms for apigenin-induced cell-cycle arrest and apoptosis of hormone refractory human prostate carcinoma DU145 cells. Mol Carcinog 2004; 39: 114–26.
Wang L, Kuang L, Hitron JA, et al. Apigenin suppresses migration and invasion of transformed cells through down-regulation of C-X-C chemokine receptor 4 expression. Toxicol Appl Pharmacol 2013; 272: 108–16.
Yan J, Wang Y, Jia Y, et al. Co-delivery of docetaxel and curcumin prodrug via dual-targeted nanoparticles with synergistic antitumor activity against prostate cancer. Biomed Pharmacother 2017; 88: 374–83.
Erdogan S, Turkekul K, Serttas R, Erdogan Z. The natural flavonoid apigenin sensitizes human CD44(+) prostate cancer stem cells to cisplatin therapy. Biomed Pharmacother 2017; 88: 210–7.
Choi EJ, Kim GH. 5-Fluorouracil combined with apigenin enhances anticancer activity through induction of apoptosis in human breast cancer MDA-MB-453 cells. Oncol Rep 2009; 22: 1533–7.
Mahbub AA, Le Maitre CL, Haywood-Small SL, et al. Polyphenols act synergistically with doxorubicin and etoposide in leukaemia cell lines. Cell Death Discov 2015; 1: 15043.
Zare MFR, Rakhshan K, Aboutaleb N, et al. Apigenin attenuates doxorubicin induced cardiotoxicity via reducing oxidative stress and apoptosis in male rats. Life Sci 2019; 232: 116623.
Sahu R, Dua TK, Das S, et al. Wheat phenolics suppress doxorubicin-induced cardiotoxicity via inhibition of oxidative stress, MAP kinase activation, NF-kappaB pathway, PI3K/Akt/mTOR impairment, and cardiac apoptosis. Food Chem Toxicol 2019; 125: 503-19.
Shukla S, Gupta S. Molecular targets for apigenin-induced cell cycle arrest and apoptosis in prostate cancer cell xenograft. Mol Cancer Ther 2006; 5: 843-52.
Zhu Y, Wu J, Li SQ, et al. Apigenin inhibits migration and invasion via modulation of epithelial mesenchymal transition in prostate cancer. Mol Med Rep 2015; 11: 1004–8.
Seo HS, Ku JM, Choi HS, et al. Apigenin overcomes drug resistance by blocking the signal transducer and activator of transcription 3 signaling in breast cancer cells. Oncol Rep 2017; 38: 715–24.
Maeda Y, Takahashi H, Nakai N, et al. Apigenin induces apoptosis by suppressing Bcl-xl and Mcl-1 simultaneously via signal transducer and activator of transcription 3 signaling in colon cancer. Int J Oncol 2018; 52: 1661–73.
Sun Q, Lu NN, Feng L. Apigetrin inhibits gastric cancer progression through inducing apoptosis and regulating ROS-modulated STAT3/JAK2 pathway. Biochem Bioph Res Commun 2018; 498: 164–70.
Korga A, Ostrowska M, Jozefczyk A, et al. Apigenin and hesperidin augment the toxic effect of doxorubicin against HepG2 cells. BMC Pharmacol Toxicol 2019; 20: 22.
Lin CC, Chuang YJ, Yu CC, et al. Apigenin induces apoptosis through mitochondrial dysfunction in U-2 OS human osteosarcoma cells and inhibits osteosarcoma xenograft tumor growth in vivo. J Agr Food Chem 2012; 60: 11395–402.
Li Y, Cheng X, Chen C, et al. Apigenin, a flavonoid constituent derived from P. villosa, inhibits hepatocellular carcinoma cell growth by CyclinD1/CDK4 regulation via p38 MAPK-p21 signaling. Pathol Res Pract 2020; 216: 152701.
Tong JF, Shen Y, Zhang ZH, et al. Apigenin inhibits epithelial-mesenchymal transition of human colon cancer cells through NF-kappa B/Snail signaling pathway. Biosci Rep 2019; 39: BSR20190452.
Tacar O, Sriamornsak P, Dass CR. Doxorubicin: an update on anticancer molecular action, toxicity and novel drug delivery systems. J Pharm Pharmacol 2013; 65: 157–70.
Shukla S, Bhaskaran N, Babcook MA, et al. Apigenin inhibits prostate cancer progression in TRAMP mice via targeting PI3K/Akt/FoxO pathway. Carcinogenesis 2014; 35: 452–60.
Lim H, Park H, Kim HP. Effects of Flavonoids on matrix metalloproteinase-13 expression of interleukin-1 beta-treated articular chondrocytes and their cellular mechanisms: inhibition of c-Fos/AP-1 and JAK/STAT signaling pathways. J Pharmacol Sci 2011; 116: 221–31.
Erdogan S, Turkekul K, Dibirdik I, et al. Midkine silencing enhances the anti-prostate cancer stem cell activity of the flavone apigenin: cooperation on signaling pathways regulated by ERK, p38, PTEN, PARP, and NF-kappaB. Invest New Drugs 2020; 38: 246–63.
Xu M, Wang SS, Song Y, et al. Apigenin suppresses colorectal cancer cell proliferation, migration and invasion via inhibition of the Wnt/beta-catenin signaling pathway. Oncol Lett 2016; 11: 3075–80.
Otto T, Sicinski P. Cell cycle proteins as promising targets in cancer therapy. Nat Rev Cancer 2017; 17: 93–115.
Erdogan S, Turkekul K. Neferine inhibits proliferation and migration of human prostate cancer stem cells through p38 MAPK/JNK activation. J Food Biochem 2020; 44: e13252.
Gupta S, Afaq F, Mukhtar H. Involvement of nuclear factor-kappa B, Bax and Bcl-2 in induction of cell cycle arrest and apoptosis by apigenin in human prostate carcinoma cells. Oncogene 2002; 21: 3727–38.
Bar-On O, Shapira M, Hershko DD. Differential effects of doxorubicin treatment on cell cycle arrest and Skp2 expression in breast cancer cells. Anti-Cancer Drug 2007; 18: 1113–21.
Kim HS, Lee YS, Kim DK. Doxorubicin exerts cytotoxic effects through cell cycle arrest and fas-mediated cell death. Pharmacology 2009; 84: 300–9.
Yan XH, Qi M, Li PF, et al. Apigenin in cancer therapy: anti-cancer effects and mechanisms of action. Cell Biosci 2017; 7.
Piska K, Koczurkiewicz P, Wnuk D, et al. Synergistic anticancer activity of doxorubicin and piperlongumine on DU-145 prostate cancer cells — The involvement of carbonyl reductase 1 inhibition. Chem-Biol Interact 2019; 300: 40–8.
Jin XX, Wei YZ, Liu YS, et al. Resveratrol promotes sensitization to doxorubicin by inhibiting epithelial-mesenchymal transition and modulating SIRT1/beta-catenin signaling pathway in breast cancer. Cancer Med 2019; 8: 1246–57.
Wang L, Kuang LS, Hitron JA, et al. Apigenin suppresses migration and invasion of transformed cells through down-regulation of C-X-C chemokine receptor 4 expression. Toxicol Appl Pharm 2013; 272: 108–16.
Trotman LC, Alimonti A, Scaglioni PP, et al. Identification of a tumour suppressor network opposing nuclear Akt function. Nature 2006; 441: 523–7.
Smith BN, Odero-Marah VA. The role of Snail in prostate cancer. Cell Adhes Migr 2012; 6: 433–41.
Erdogan S, Doganlar O, Doganlar ZB, Turkekul K. Naringin sensitizes human prostate cancer cells to paclitaxel therapy. Prostate Int 2018; 6: 126–35.
Lin YW, Kang TB, Zhou BHP. Doxorubicin enhances Snail/LSD1-mediated PTEN suppression in a PARP1-dependent manner. Cell Cycle 2014; 13: 1708–16.
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