Anti-proliferative effects of paeonol on human prostate cancer cell lines DU145 and PC-3
Tóm tắt
Paeonol (Pae) is the main active ingredient from the root bark of Paeonia moutan and the grass of Radix Cynanchi Paniculati. Numerous reports indicate that Pae effectively inhibits several types of cancer lines. In this study, we report that Pae hinders prostate cancer growth both in vivo and in vitro. Human prostate cancer lines DU145 and PC-3 were cultured in the presence of Pae. The xenograft tumor in mice was established by subcutaneous injection of DU145 cells. Cell growth was measured by MTT, and the apoptosis was detected by the flow cytometry. Expression of Bcl-2, Bax, Akt, and mTOR were tested by western blotting assay. DU145 and PC-3 showed remarkable sensitivity to Pae, and exposure to Pae induced dose-and time-dependent growth inhibitory responses. Moreover, treatment of Pae promoted apoptosis and enhanced activities of caspase-3, caspase-8, and caspase-9 in DU145. Further work demonstrated Pae reduced expression of Bcl-2 and increased expression of Bax in DU145. Interestingly, we observed that Pae significantly decreased phosphorylated status of Akt and mTOR, and inhibitory effects of Pae and PI3K/Akt inhibitor on DU145 proliferation were synergistic. Finally, we confirmed that oral administration of Pae to the DU145 tumor-bearing mice significantly lowered tumor cell proliferation and led to tumor regression. Pae possesses inhibitory effects on prostate cancer cell growth both in vitro and in vivo, and the anti-proliferative effect may be closely related to its activation of extrinsic and intrinsic apoptotic pathway and inhibition of the PI3K/Akt pathway.
Tài liệu tham khảo
Adams JM, Cory S (2001) Life-or-death decisions by the Bcl-2 protein family. Trends Biochem Sci 26:61–66
Bai D, Ueno L, Vogt PK (2009) Akt-mediated regulation of NFkappaB and the essentialness of NFkappaB for the oncogenicity of PI3K and Akt. Int J Cancer 125:2863–2870
Bartholomeusz C, Gonzalez-Angulo AM (2012) Targeting the PI3K signaling pathway in cancer therapy. Expert Opin Ther Targets 16:121–130
Benayoun BA, Caburet S, Veitia RA (2011) Forkhead transcription factors: key players in health and disease. Trends Genet 27:224–232
Cai J, Chen S, Zhang W, Hu S, Lu J, Xing J, Dong Y (2014) Paeonol reverses paclitaxel resistance in human breast cancer cells by regulating the expression of transgelin 2. Phytomedicine 21:984–991
Chandra D, Choy G, Deng X, Bhatia B, Daniel P, Tang DG (2004) Association of active caspase 8 with the mitochondrial membrane during apoptosis: potential roles in cleaving BAP31 and caspase 3 and mediating mitochondrion-endoplasmic reticulum cross talk in etoposide-induced cell death. Mol Cell Biol 24:6592–6607
Chunhu Z, Suiyu H, Meiqun C, Guilin X, Yunhui L (2008) Antiproliferative and apoptotic effects of paeonol on human hepatocellular carcinoma cells. Anti-Cancer Drugs 19:401–409
Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg ME (1997) Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91:231–241
Davis WJ, Lehmann PZ, Li W (2015) Nuclear PI3K signaling in cell growth and tumorigenesis. Front Cell Dev Biol 3:24
Feldman BJ, Feldman D (2001) The development of androgen-independent prostate cancer. Nat Rev Cancer 1:34–45
Goldar S, Khaniani MS, Derakhshan SM, Baradaran B (2015) Molecular mechanisms of apoptosis and roles in cancer development and treatment. Asian Pac J Cancer Prev 16:2129–2144
Green DR, Llambi F (2015) Cell death signaling. Cold Spring Harb Perspect Biol 7(12) pii: a006080. doi:10.1101/cshperspect.a006080
He CN, Peng Y, Zhang YC, Xu LJ, Gu J, Xiao PG (2010) Phytochemical and biological studies of paeoniaceae. Chem Biodivers 7:805–838
Hilal L, Shahait M, Mukherji D, Charafeddine M, Farhat Z, Temraz S, Khauli R, Shamseddine A (2015) Prostate cancer in the Arab world: a view from the inside. Clin Genitourin Cancer 13:505–511
Horng CT, Shieh PC, Tan TW, Yang WH, Tang CH (2014) Paeonol suppresses chondrosarcoma metastasis through up-regulation of miR-141 by modulating PKCδ and c-Src signaling pathway. Int J Mol Sci 15:11760–11772
Jemal A, Siegel R, Xu J, Ward E (2010) Cancer statistics, 2010. CA Cancer J Clin 60:277–300
Kar S, Palit S, Ball WB, Das PK (2012) Carnosic acid modulates Akt/IKK/NF-κB signaling by PP2A and induces intrinsic and extrinsic pathway mediated apoptosis in human prostate carcinoma PC-3 cells. Apoptosis 17:735–747
Li M, Tan SY, Zhang J, You HX (2013) Effects of paeonol on intracellular calcium concentration and expression of RUNX3 in LoVo human colon cancer cells. Mol Med Rep 7:1425–1430
Li M, Tan SY, Wang XF (2014) Paeonol exerts an anticancer effect on human colorectal cancer cells through inhibition of PGE2 synthesis and COX-2 expression. Oncol Rep 32:2845–2853
Lima AP, Pereira FC, Almeida MA, Mello FM, Pires WC, Pinto TM, Delella FK, Felisbino SL, Moreno V, Batista AA, de Paula S-LE (2014) Cytoxicity and apoptotic mechanism of ruthenium(II) amino acid complexes in sarcoma-180 tumor cells. PLoS One 9:e105865
Li N, Fan LL, Sun GP, Wan XA, Wang ZG, Wu Q, Wang H (2010) Paeonol inhibits tumor growth in gastric cancer in vitro and in vivo. World J Gastroenterol 16:4483–4490
Li Y, Li P, Lin SH, Zheng YQ, Zheng XX (2014) Paeonol inhibited TNF-alpha-induced GM-CSF expression in fibroblast-like synoviocytes. Int J Clin Pharmacol Ther 52:986–996
Sangawa A, Shintani M, Yamao N, Kamoshida S (2014) Phosphorylation status of Akt and caspase-9 in gastric and colorectal carcinomas. Int J Clin Exp Pathol 7:3312–3317
Siegel R, Ward E, Brawley O, Jemal A (2011) Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin 61:212–236
Singh SS, Yap WN, Arfuso F, Kar S, Wang C, Cai W, Dharmarajan AM, Sethi G, Kumar AP (2015) Targeting the PI3K/Akt signaling pathway in gastric carcinoma: a reality for personalized medicine? World J Gastroenterol 21:12261–12273
Sun GP, Wan X, Xu SP, Wang H, Liu SH, Wang ZG (2008) Antiproliferation and apoptosis induction of paeonol in human esophageal cancer cell lines. Dis Esophagus 21:723–729
Tang L, Jin T, Zeng X, Wang JS (2005) Lycopene inhibits the growth of human androgen- independent prostate cancer cells in vitro and in BALB/c nude mice. J Nutr 135:287–290
Tan S, Ye J, Qian C, Ji C, Liu C, Wang J (2007) Paeonol inhibits the proliferation of human colorectal carcinoma cells and synergic with chemotherapeutic agents. Saudi Med J 28:642–643
Xie Y, Zhou H, Wong YF, Xu HX, Jiang ZH, Liu L (2008) Study on the pharmacokinetics and metabolism of paeonol in rats treated with pure paeonol and an herbal preparation containing paeonol by using HPLC-DAD-MS method. J Pharm Biomed Anal 46:748–756
Xing G, Zhang Z, Liu J, Hu H, Sugiura N (2010) Antitumor effect of extracts from moutan cortex on DLD-1 human colon cancer cells in vitro. Mol Med Rep 3:57–61
Xu SP, Sun GP, Shen YX, Wei W, Peng WR, Wang H (2007) Antiproliferation and apoptosis induction of paeonol in HepG2 cells. World J Gastroenterol 13:250–256
Xu SP, Sun GP, Shen YX, Peng WR, Wang H, Wei W (2007) Synergistic effect of combining paeonol and cisplatin on apoptotic induction of human hepatoma cell lines. Acta Pharmacol Sin 28:869–878
Ye JM, Deng T, Zhang JB (2009) Influence of paeonol on expression of COX-2 and p27 in HT-29 cells. World J Gastroenterol 15:4410–4414
Yin J, Wu N, Zeng F, Cheng C, Kang K, Yang H (2013) Paeonol induces apoptosis in human ovarian cancer cells. Acta Histochem 115:835–839
Zhang L, Tao L, Shi T, Zhang F, Sheng X, Cao Y, Zheng S, Wang A, Qian W, Jiang L, Lu Y (2015) Paeonol inhibits B16F10 melanoma metastasis in vitro and in vivo via disrupting proinflammatory cytokines-mediated NF-κB and STAT3 pathways. IUBMB Life 67:778–788
Zhang W, Cai J, Chen S, Zheng X, Hu S, Dong W, Lu J, Xing J, Dong Y (2015) Paclitaxel resistance in MCF-7/PTX cells is reversed by paeonol through suppression of the SET/phosphatidylinositol 3-kinase/Akt pathway. Mol Med Rep 12:1506–1514