BAI, a novel Cdk inhibitor, enhances farnesyltransferase inhibitor LB42708-mediated apoptosis in renal carcinoma cells through the downregulation of Bcl-2 and c-FLIP (L)

Jang,Ji Hoon; Cho,Yoon Chul; Kim,Ki Ho; Lee,Kyung Seop; Lee,Jinho; Kim,Dong Eun; Park,Jun-Soo; Jang,Byeong-Churl; Kim,Shin; Kwon,Taeg Kyu; Park,Jong-Wook

doi:10.3892/ijo.2014.2534

BAI, a novel Cdk inhibitor, enhances farnesyltransferase inhibitor LB42708-mediated apoptosis in renal carcinoma cells through the downregulation of Bcl-2 and c-FLIP (L)

Authors:
- Ji Hoon Jang
- Yoon Chul Cho
- Ki Ho Kim
- Kyung Seop Lee
- Jinho Lee
- Dong Eun Kim
- Jun-Soo Park
- Byeong-Churl Jang
- Shin Kim
- Taeg Kyu Kwon
- Jong-Wook Park
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Affiliations: Department of Immunology, School of Medicine, Keimyung University, Daegu, Republic of Korea, Department of Urology, Dongguk University, College of Medicine, Gyeongju, Republic of Korea, Department of Chemistry, Keimyung University, Daegu, Republic of Korea, Chronic Disease Research Center, School of Medicine, Keimyung University, Daegu, Republic of Korea
Published online on: July 4, 2014 https://doi.org/10.3892/ijo.2014.2534
Pages: 1680-1690

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Abstract

Previously, we reported the potential of a novel Cdk inhibitor, 2-[1,1'-biphenyl]-4-yl-N-[5-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide (BAI) as a cancer chemotherapeutic agent. In this study, we investigated mechanisms by which BAI modulates FTI-mediated apoptosis in human renal carcinoma Caki cells. BAI synergizes with FTI to activate DEVDase, cleavage of poly ADP-ribose polymerase (PARP), and degradation of various anti-apoptotic proteins in Caki cells. BAI plus LB42708-induced apoptosis was inhibited by pretreatment with pan-caspase inhibitor, z-VAD-fmk, but not by overexpression of CrmA. The ROS scavenger, N-acetylcysteine (NAC) did not reduce BAI plus LB4270-induced apoptosis. Co-treatment of BAI and LB42708 reduced the mitochondrial membrane potential (MMP, ∆Ψm) in a time-dependent manner, and induced release of AIF and cytochrome c from mitochondria in Caki cells. Furthermore, BAL plus LB42708 induced downregulation of anti-apoptotic proteins [c-FLIP (L), c-FLIP (s), Bcl-2, XIAP, and Mcl-1 (L)]. Especially, we found that BAI plus LB42708-induced apoptosis was significantly attenuated by overexpression of Bcl-2 and partially blocked by overexpression of c-FLIP (L). Taken together, our results show that the activity of BAI plus LB42708 modulate multiple components in apoptotic response of human renal Caki cells, and indicate a potential as combinational therapeutic agents for preventing cancer such as renal carcinoma.

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1	Malumbres M and Barbacid M: To cycle or not to cycle: a critical decision in cancer. Nat Rev Cancer. 1:222–231. 2001. View Article : Google Scholar : PubMed/NCBI
2	Lee J, Choi H, Kim KH, et al: Synthesis and biological evaluation of 3,5-diaminoindazoles as cyclin-dependent kinase inhibitors. Bioorg Med Chem Lett. 18:2292–2295. 2008. View Article : Google Scholar : PubMed/NCBI
3	Shin HC, Song DW, Baek WK, et al: Anticancer activity and differentially expressed genes in head and neck cancer cells treated with a novel cyclin-dependent kinase inhibitor. Chemotherapy. 55:353–362. 2009. View Article : Google Scholar : PubMed/NCBI
4	Kim S, Lee J, Jang BC, Kwon TK and Park JW: BAI, a novel cyclin-dependent kinase inhibitor induces apoptosis in A549 cells through activation of caspases and inactivation of Akt. J Cell Biochem. 114:282–293. 2013. View Article : Google Scholar : PubMed/NCBI
5	Bharate SB, Singh B and Vishwakarma RA: Modulation of K-Ras signaling by natural products. Curr Med Chem. 19:2273–2291. 2012.PubMed/NCBI
6	Almoguera C, Shibata D, Forrester K, Martin J, Arnheim N and Perucho M: Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell. 53:549–554. 1988. View Article : Google Scholar : PubMed/NCBI
7	Nelson MA, Wymer J and Clements N Jr: Detection of K-ras gene mutations in non-neoplastic lung tissue and lung cancers. Cancer Lett. 103:115–121. 1996. View Article : Google Scholar : PubMed/NCBI
8	Gibbs JB, Oliff A and Kohl NE: Farnesyltransferase inhibitors: Ras research yields a potential cancer therapeutic. Cell. 77:175–178. 1994. View Article : Google Scholar : PubMed/NCBI
9	Tamanoi F: Inhibitors of Ras farnesyltransferases. Trends Biochem Sci. 18:349–353. 1993. View Article : Google Scholar : PubMed/NCBI
10	Travis J: Novel anticancer agents move closer to reality. Science. 260:1877–1878. 1993. View Article : Google Scholar : PubMed/NCBI
11	Carloni V, Vizzutti F and Pantaleo P: Farnesyltransferase inhibitor, ABT-100, is a potent liver cancer chemopreventive agent. Clin Cancer Res. 11:4266–4274. 2005. View Article : Google Scholar : PubMed/NCBI
12	Lin NH, Wang L, Cohen J, et al: Synthesis and biological evaluation of 4-[(3-methyl-3H-imidazol-4-yl)-(2-phenylethynyl-benzyloxy)- methyl]-benzonitrile as novel farnesyltransferase inhibitor. Bioorg Med Chem Lett. 13:3821–3825. 2003.
13	Lin NH, Wang L, Wang X, et al: Synthesis and biological evaluation of 1-benzyl-5-(3-biphenyl-2-yl-propyl)-1H-imidazole as novel farnesyltransferase inhibitor. Bioorg Med Chem Lett. 14:5057–5062. 2004. View Article : Google Scholar : PubMed/NCBI
14	Kim HS, Kim JW, Gang J, et al: The farnesyltransferase inhibitor, LB42708, inhibits growth and induces apoptosis irreversibly in H-ras and K-ras-transformed rat intestinal epithelial cells. Toxicol Appl Pharmacol. 215:317–329. 2006. View Article : Google Scholar : PubMed/NCBI
15	Balasis ME, Forinash KD, Chen YA, et al: Combination of farnesyltransferase and Akt inhibitors is synergistic in breast cancer cells and causes significant breast tumor regression in ErbB2 transgenic mice. Clin Cancer Res. 17:2852–2862. 2011. View Article : Google Scholar : PubMed/NCBI
16	Krzykowska-Petitjean K, Malecki J, Bentke A, Ostrowska B and Laidler P: Tipifarnib and tanespimycin show synergic proapoptotic activity in U937 cells. J Cancer Res Clin Oncol. 138:537–544. 2012. View Article : Google Scholar : PubMed/NCBI
17	Sackova V, Kulikova L, Kello M, Uhrinova I and Fedorocko P: Enhanced antiproliferative and apoptotic response of HT-29 adenocarcinoma cells to combination of photoactivated hypericin and farnesyltransferase inhibitor manumycin A. Int J Mol Sci. 12:8388–8405. 2011. View Article : Google Scholar
18	Edamatsu H, Gau CL, Nemoto T, Guo L and Tamanoi F: Cdk inhibitors, roscovitine and olomoucine, synergize with farnesyltransferase inhibitor (FTI) to induce efficient apoptosis of human cancer cell lines. Oncogene. 19:3059–3068. 2000. View Article : Google Scholar : PubMed/NCBI
19	Lee H, Lee J, Lee S, et al: A novel class of highly potent, selective, and non-peptidic inhibitor of Ras farnesyltransferase (FTase). Bioorg Med Chem Lett. 11:3069–3072. 2001. View Article : Google Scholar : PubMed/NCBI
20	Hetz C: The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat Rev Mol Cell Biol. 13:89–102. 2012.PubMed/NCBI
21	Simon HU, Haj-Yehia A and Levi-Schaffer F: Role of reactive oxygen species (ROS) in apoptosis induction. Apoptosis. 5:415–418. 2000. View Article : Google Scholar : PubMed/NCBI
22	Le Bras M, Rouy I and Brenner C: The modulation of interorganelle cross-talk to control apoptosis. Med Chem. 2:1–12. 2006.PubMed/NCBI
23	Bodur C and Basaga H: Bcl-2 inhibitors: emerging drugs in cancer therapy. Curr Med Chem. 19:1804–1820. 2012. View Article : Google Scholar : PubMed/NCBI
24	Ili CG, Brebi P, Tapia O, et al: Cellular FLICE-like inhibitory protein long form (c-FLIPL) overexpression is related to cervical cancer progression. Int J Gynecol Pathol. 32:316–322. 2013. View Article : Google Scholar : PubMed/NCBI
25	Khosravi-Far R and Der CJ: The Ras signal transduction pathway. Cancer Metastasis Rev. 13:67–89. 1994. View Article : Google Scholar : PubMed/NCBI
26	Cohen LH, Pieterman E, van Leeuwen RE, et al: Inhibitors of prenylation of Ras and other G-proteins and their application as therapeutics. Biochem Pharmacol. 60:1061–1068. 2000. View Article : Google Scholar : PubMed/NCBI
27	Moasser MM, Sepp-Lorenzino L, Kohl NE, et al: Farnesyl transferase inhibitors cause enhanced mitotic sensitivity to taxol and epothilones. Proc Natl Acad Sci USA. 95:1369–1374. 1998. View Article : Google Scholar : PubMed/NCBI
28	Smalley KSM and Eisen TG: Farnesyl transferase inhibitor SCH66336 is cytostatic, pro-apoptotic and enhances chemosensitivity to cisplatin in melanoma cells. Int J Cancer. 105:165–175. 2003. View Article : Google Scholar : PubMed/NCBI
29	Wesierska-Gadek J, Maurer M and Schmid G: Inhibition of farnesyl protein transferase sensitizes human MCF-7 breast cancer cells to roscovitine-mediated cell cycle arrest. J Cell Biochem. 102:736–747. 2007. View Article : Google Scholar : PubMed/NCBI
30	Singha PK, Pandeswara S, Venkatachalam MA and Saikumar P: Manumycin A inhibits triple-negative breast cancer growth through LC3-mediated cytoplasmic vacuolation death. Cell Death Dis. 4:e4572013. View Article : Google Scholar : PubMed/NCBI
31	Mahoney E, Lucas DM, Gupta SV, et al: ER stress and autophagy: new discoveries in the mechanism of action and drug resistance of the cyclin-dependent kinase inhibitor flavopiridol. Blood. 120:1262–1273. 2012. View Article : Google Scholar : PubMed/NCBI
32	Kuo PL, Chen CY and Hsu YL: Isoobtusilactone A induces cell cycle arrest and apoptosis through reactive oxygen species/apoptosis signal-regulating kinase 1 signaling pathway in human breast cancer cells. Cancer Res. 67:7406–7420. 2007. View Article : Google Scholar
33	Yodkeeree S, Sung B, Limtrakul P and Aggarwal BB: Zerumbone enhances TRAIL-induced apoptosis through the induction of death receptors in human colon cancer cells: Evidence for an essential role of reactive oxygen species. Cancer Res. 69:6581–6589. 2009. View Article : Google Scholar
34	Min KJ, Kim HS, Park EJ and Kwon TK: Melatonin enhances thapsigargin-induced apoptosis through reactive oxygen species-mediated upregulation of CCAAT-enhancer-binding protein homologous protein in human renal cancer cells. J Pineal Res. 53:99–106. 2012. View Article : Google Scholar
35	She M, Yang H, Sun L and Yeung SC: Redox control of manumycin A-induced apoptosis in anaplastic thyroid cancer cells: involvement of the xenobiotic apoptotic pathway. Cancer Biol Ther. 5:275–280. 2006. View Article : Google Scholar : PubMed/NCBI
36	Pan J, She M, Xu ZX, Sun L and Yeung SC: Farnesyltransferase inhibitors induce DNA damage via reactive oxygen species in human cancer cells. Cancer Res. 65:3671–3681. 2005. View Article : Google Scholar : PubMed/NCBI
37	Slee EA, Zhu H, Chow SC, MacFarlane M, Nicholson DW and Cohen GM: Benzyloxycarbonyl-Val-Ala-Asp (OMe) fluoromethylketone (Z-VAD.FMK) inhibits apoptosis by blocking the processing of CPP32. Biochem J. 315:21–24. 1996.PubMed/NCBI
38	Yang B, El Nahas AM, Fisher M, et al: Inhibitors directed towards caspase-1 and -3 are less effective than pan caspase inhibition in preventing renal proximal tubular cell apoptosis. Nephron Exp Nephrol. 96:e39–e51. 2004. View Article : Google Scholar : PubMed/NCBI
39	Yang PM, Tseng HH, Peng CW, Chen WS and Chiu SJ: Dietary flavonoid fisetin targets caspase-3-deficient human breast cancer MCF-7 cells by induction of caspase-7-associated apoptosis and inhibition of autophagy. Int J Oncol. 40:469–478. 2012.PubMed/NCBI
40	Sawai H: Differential effects of caspase inhibitors on TNF-induced necroptosis. Biochem Biophys Res Commun. 432:451–455. 2013. View Article : Google Scholar : PubMed/NCBI
41	Uchiyama R, Kawamura I, Fujimura T, et al: Involvement of caspase-9 in the inhibition of necrosis of RAW 264 cells infected with Mycobacterium tuberculosis. Infect Immun. 75:2894–2902. 2007. View Article : Google Scholar : PubMed/NCBI
42	Zhou Q, Snipas S, Orth K, Muzio M, Dixit VM and Salvesen GS: Target protease specificity of the viral serpin CrmA. Analysis of five caspases. J Biol Chem. 272:7797–7800. 1997. View Article : Google Scholar : PubMed/NCBI
43	Garcia-Calvo M, Peterson EP, Leiting B, Ruel R, Nicholson DW and Thornberry NA: Inhibition of human caspases by peptide-based and macromolecular inhibitors. J Biol Chem. 273:32608–32613. 1998. View Article : Google Scholar : PubMed/NCBI
44	Schimmer AD, Dalili S, Batey RA and Riedl SJ: Targeting XIAP for the treatment of malignancy. Cell Death Differ. 13:179–188. 2006. View Article : Google Scholar : PubMed/NCBI
45	Zinkel S, Gross A and Yang E: BCL2 family in DNA damage and cell cycle control. Cell Death Differ. 13:1351–1359. 2006. View Article : Google Scholar : PubMed/NCBI
46	Jonsson G, Paulie S and Grandien A: High level of cFLIP correlates with resistance to death receptor-induced apoptosis in bladder carcinoma cells. Anticancer Res. 23:1213–1218. 2003.PubMed/NCBI
47	Longley DB, Wilson TR, McEwan M, et al: c-FLIP inhibits chemotherapy-induced colorectal cancer cell death. Oncogene. 25:838–848. 2006. View Article : Google Scholar : PubMed/NCBI
48	Thomas S, Quinn BA, Das SK, et al: Targeting the Bcl-2 family for cancer therapy. Expert Opin Ther Targets. 17:61–75. 2013. View Article : Google Scholar