Bufalin sensitizes human bladder carcinoma cells to TRAIL-mediated apoptosis

Kang,Kyung‑Hwa; Han,Min  Ho; Jeong,Jin‑Woo; Park,Cheol; Lee,Sang‑Hyup; Lee,Hai  Woong; Hong,Sang  Hoon; Choi,Yung  Hyun; Hong,Su  Hyun

doi:10.3892/ol.2017.6223

Bufalin sensitizes human bladder carcinoma cells to TRAIL-mediated apoptosis

Authors:
- Kyung‑Hwa Kang
- Min Ho Han
- Jin‑Woo Jeong
- Cheol Park
- Sang‑Hyup Lee
- Hai Woong Lee
- Sang Hoon Hong
- Yung Hyun Choi
- Su Hyun Hong
View Affiliations

Affiliations: Department of Physiology, Dongeui University College of Korean Medicine, Busan 614‑052, Republic of Korea, Natural Products Research Team, National Marine Biodiversity Institute of Korea, Seocheon, South Chungcheong 325‑902, Republic of Korea, Department of Biochemistry, Dongeui University College of Korean Medicine, Busan 614‑052, Republic of Korea, Department of Molecular Biology, College of Natural Science and Human Ecology, Dongeui University, Busan 614‑714, Republic of Korea, Department of Korean Medical Classics, Dongeui University College of Korean Medicine, Busan 614‑052, Republic of Korea, Department of Public Health, Dongeui University College of Korean Medicine, Busan 614‑052, Republic of Korea, Department of Internal Medicine, Dongeui University College of Korean Medicine, Busan 614‑052, Republic of Korea
Published online on: May 22, 2017 https://doi.org/10.3892/ol.2017.6223
Pages: 853-859
Copyright: © Kang 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

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily, has garnered interest as it is relatively non‑toxic to normal cells, but selectively induces apoptotic cell death in multiple types of transformed or malignant cells. Bufalin is the major digoxin‑like immunoreactive component of Sum Su, which is obtained from the skin and parotid venom gland of the toad. Bufalin is known to inhibit cell proliferation and induce apoptosis in a variety of cancer cells. The present study investigated whether bufalin promoted TRAIL‑induced apoptotic cell death. In the present study, a combined treatment using bufalin and TRAIL significantly increased TRAIL‑mediated inhibition of cell viability and increased apoptosis in T24 human bladder cancer cells. The apoptotic effects were associated with the upregulation of death receptor proteins and the downregulation of cellular Fas‑associated death domain-like interleukin‑1β‑converting enzyme inhibitory protein and X‑linked inhibitor of apoptosis protein. Furthermore, the data revealed that bufalin and TRAIL activated caspase‑3, ‑8 and ‑9 and subsequently increased the degradation of poly (ADP‑ribose) polymerase. Taken altogether, the nontoxic doses of bufalin and TRAIL sensitized T24 cells to TRAIL‑mediated apoptosis. Therefore, bufalin may provide an effective therapeutic strategy for the safe treatment of human bladder cancers that are resistant to TRAIL.

View Figures

View References

1	Trivedi R and Mishra DP: Trailing TRAIL resistance: Novel targets for TRAIL sensitization in cancer cells. Front Oncol. 5:692015. View Article : Google Scholar : PubMed/NCBI
2	Thorburn A, Behbakht K and Ford H: TRAIL receptor-targeted therapeutics: Resistance mechanisms and strategies to avoid them. Drug Resist Updat. 11:17–24. 2008. View Article : Google Scholar : PubMed/NCBI
3	Dai X, Zhang J, Arfuso F, Chinnathambi A, Zayed ME, Alharbi SA, Kumar AP, Ahn KS and Sethi G: Targeting TNF-related apoptosis-inducing ligand (TRAIL) receptor by natural products as a potential therapeutic approach for cancer therapy. Exp Biol Med (Maywood). 240:760–773. 2015. View Article : Google Scholar : PubMed/NCBI
4	Szliszka E, Mazur B, Zydowicz G, Czuba ZP and Król W: TRAIL-induced apoptosis and expression of death receptor TRAIL-R1 and TRAIL-R2 in bladder cancer cells. Folia Histochem Cytobiol. 47:579–585. 2009.PubMed/NCBI
5	Lim B, Allen JE, Prabhu VV, Talekar MK, Finnberg NK and El-Deiry WS: Targeting TRAIL in the treatment of cancer: New developments. Expert Opin Ther Targets. 19:1171–1185. 2015. View Article : Google Scholar : PubMed/NCBI
6	Chen S, Fu L, Raja SM, Yue P, Khuri FR and Sun SY: Dissecting the roles of DR4, DR5 and c-FLIP in the regulation of Geranylgeranyltransferase I inhibition-mediated augmentation of TRAIL-induced apoptosis. Mol Cancer. 9:232010. View Article : Google Scholar : PubMed/NCBI
7	Wang S and El-Deiry WS: TRAIL and apoptosis induction by TNF-family death receptors. Oncogene. 22:8628–8633. 2003. View Article : Google Scholar : PubMed/NCBI
8	Guancial EA, Roussel B, Bergsma DP, Bylund KC, Sahasrabudhe D, Messing E, Mohile SG and Fung C: Bladder cancer in the elderly patient: Challenges and solutions. Clin Interv Aging. 10:939–949. 2015.PubMed/NCBI
9	Shamseddine A, Saleh A, Charafeddine M, Seoud M, Mukherji D, Temraz S and Sibai AM: Cancer trends in Lebanon: A review of incidence rates for the period of 2003–2008 and projections until 2018. Popul Health Metr. 12:42014. View Article : Google Scholar : PubMed/NCBI
10	Ahmed SM, Wu X, Jin X, Zhang X, Togo Y, Suzuki T, Li Y, Kanematsu A, Nojima M, Yamamoto S, et al: Synergistic induction of apoptosis by mapatumumab and anthracyclines in human bladder cancer cells. Oncol Rep. 33:566–572. 2015.PubMed/NCBI
11	Ploeg M, Aben KK and Kiemeney LA: The present and future burden of urinary bladder cancer in the world. World J Urol. 27:289–293. 2009. View Article : Google Scholar : PubMed/NCBI
12	Yan S, Qu X, Xu L, Che X, Ma Y, Zhang L, Teng Y, Zou H and Liu Y: Bufalin enhances TRAIL-induced apoptosis by redistributing death receptors in lipid rafts in breast cancer cells. Anticancer Drugs. 25:683–689. 2014.PubMed/NCBI
13	White-Gilbertson SJ, Kasman L, McKillop J, Tirodkar T, Lu P and Voelkel-Johnson C: Oxidative stress sensitizes bladder cancer cells to TRAIL mediated apoptosis by down-regulating anti-apoptotic proteins. J Urol. 182:1178–1185. 2009. View Article : Google Scholar : PubMed/NCBI
14	LeBlanc H, Lawrence D, Varfolomeev E, Totpal K, Morlan J, Schow P, Fong S, Schwall R, Sinicropi D and Ashkenazi A: Tumor-cell resistance to death receptor-induced apoptosis through mutational inactivation of the proapoptotic Bcl-2 homolog Bax. Nat Med. 8:274–281. 2002. View Article : Google Scholar : PubMed/NCBI
15	Shi YL, Feng S, Chen W, Hua ZC, Bian JJ and Yin W: Mitochondrial inhibitor sensitizes non-small-cell lung carcinoma cells to TRAIL-induced apoptosis by reactive oxygen species and Bcl-X(L)/p53-mediated amplification mechanisms. Cell Death Dis. 5:e15792014. View Article : Google Scholar : PubMed/NCBI
16	Yin PH, Liu X, Qiu YY, Cai JF, Qin JM, Zhu HR and Li Q: Anti-tumor activity and apoptosis-regulation mechanisms of bufalin in various cancers: New hope for cancer patients. Asian Pac J Cancer Prev. 13:5339–5343. 2012. View Article : Google Scholar : PubMed/NCBI
17	Qi F, Li A, Inagaki Y, Kokudo N, Tamura S, Nakata M and Tang W: Antitumor activity of extracts and compounds from the skin of the toad Bufo bufo gargarizans Cantor. Int Immunopharmacol. 11:342–349. 2011. View Article : Google Scholar : PubMed/NCBI
18	Huang WW, Yang JS, Pai SJ, Wu PP, Chang SJ, Chueh FS, Fan MJ, Chiou SM, Kuo HM, Yeh CC, et al: Bufalin induces G0/G1 phase arrest through inhibiting the levels of cyclin Dcyclin E, CDK2 and CDK4, and triggers apoptosis via mitochondrial signaling pathway in T24 human bladder cancer cells. Mutat Res. 732:26–33. 2012. View Article : Google Scholar : PubMed/NCBI
19	Takai N, Ueda T, Nishida M, Nasu K and Narahara H: Bufalin induces growth inhibition, cell cycle arrest and apoptosis in human endometrial and ovarian cancer cells. Int J Mol Med. 21:637–643. 2008.PubMed/NCBI
20	Yeh JY, Huang WJ, Kan SF and Wang PS: Effects of bufalin and cinobufagin on the proliferation of androgen dependent and independent prostate cancer cells. Prostate. 54:112–124. 2003. View Article : Google Scholar : PubMed/NCBI
21	Yan S, Qu X, Xu C, Zhu Z, Zhang L, Xu L, Song N, Teng Y and Liu Y: Down-regulation of Cbl-b by bufalin results in up-regulation of DR4/DR5 and sensitization of TRAIL-induced apoptosis in breast cancer cells. J Cancer Res Clin Oncol. 138:1279–1289. 2012. View Article : Google Scholar : PubMed/NCBI
22	Kelley RF, Totpal K, Lindstrom SH, Mathieu M, Billeci K, Deforge L, Pai R, Hymowitz SG and Ashkenazi A: Receptor-selective mutants of apoptosis-inducing ligand 2/tumor necrosis factor- related apoptosis-inducing ligand reveal a greater contribution of death receptor (DR) 5 than DR4 to apoptosis signaling. J Biol Chem. 280:2205–2212. 2005. View Article : Google Scholar : PubMed/NCBI
23	Yin XM: Signal transduction mediated by Bid, a pro-death Bcl-2 family proteins, connects the death receptor and mitochondria apoptosis pathways. Cell Res. 10:161–167. 2000. View Article : Google Scholar : PubMed/NCBI
24	Shalini S, Dorstyn L, Dawar S and Kumar S: Old, new and emerging functions of caspases. Cell Death Differ. 22:526–539. 2015. View Article : Google Scholar : PubMed/NCBI
25	Jin CY, Park C, Hwang HJ, Kim GY, Choi BT, Kim WJ and Choi YH: Naringenin up-regulates the expression of death receptor 5 and enhances TRAIL-induced apoptosis in human lung cancer A549 cells. Mol Nutr Food Res. 55:300–309. 2011. View Article : Google Scholar : PubMed/NCBI
26	Hong SH and Choi YH: Bufalin induces apoptosis through activation of both the intrinsic and extrinsic pathways in human bladder cancer cells. Oncol Rep. 27:114–120. 2012.PubMed/NCBI
27	Li Y, Jin X, Li J, Jin X, Yu J, Sun X, Chu Y, Xu C, Li X, Wang X, et al: Expression of TRAIL, DR4, and DR5 in bladder cancer: Correlation with response to adjuvant therapy and implications of prognosis. Urology. 79:968.e7–e15. 2012. View Article : Google Scholar
28	Wu GS: TRAIL as a target in anti-cancer therapy. Cancer Lett. 285:1–5. 2009. View Article : Google Scholar : PubMed/NCBI
29	Chen Z, Sangwan V, Banerjee S, Chugh R, Dudeja V, Vickers SM and Saluja AK: Triptolide sensitizes pancreatic cancer cells to TRAIL-induced activation of the death receptor pathway. Cancer Lett. 348:156–166. 2014. View Article : Google Scholar : PubMed/NCBI
30	Safa AR: c-FLIP, a master anti-apoptotic regulator. Exp Oncol. 34:176–184. 2012.PubMed/NCBI
31	Ewald F, Ueffing N, Brockmann L, Hader C, Telieps T, Schuster M, Schulz WA and Schmitz I: The role of c-FLIP splice variants in urothelial tumours. Cell Death Dis. 2:e2452011. View Article : Google Scholar : PubMed/NCBI