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Article

A novel HDAC inhibitor OBP-801 and a PI3K inhibitor LY294002 synergistically induce apoptosis via the suppression of survivin and XIAP in renal cell carcinoma

  • Authors:
    • Takeshi Yamada
    • Mano Horinaka
    • Masahide Shinnoh
    • Takashi Yoshioka
    • Tsuneharu Miki
    • Toshiyuki Sakai
  • View Affiliations / Copyright

    Affiliations: Department of Molecular-Targeting Cancer Prevention, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan, Department of Urology, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
  • Pages: 1080-1086
    |
    Published online on: July 30, 2013
       https://doi.org/10.3892/ijo.2013.2042
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Abstract

Renal cell carcinoma (RCC) is resistant to traditional cancer therapies such as radiation therapy and chemotherapy. The use of targeted therapies has improved the clinical outcomes of patients with metastatic RCC. However, most patients acquire resistance against targeted therapies over time. We report that the combination of the novel histone deacetylase (HDAC) inhibitor OBP-801, also known as YM753 and the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 synergistically inhibits cell growth and induces apoptosis in RCC cells. This combination activated caspase-3, -8 and -9 and the pan-caspase inhibitor zVAD-fmk significantly reduced the apoptotic response to the treatment with OBP-801 and LY294002. Moreover, the combined treatment induced intracellular reactive oxygen species (ROS) and the radical scavenger N-acetyl-L-cysteine (NAC) blocked the intracellular ROS and apoptosis induced by OBP-801 and LY294002. The co-treatment with OBP-801 and LY294002 markedly decreased survivin and the X-linked inhibitor of apoptosis protein (XIAP) protein levels, but Bcl-2 family members were not altered by the OBP-801/LY294002 co-treatment. These alterations were restored by NAC treatment. The transient transfection of survivin and XIAP reduced the apoptotic response to the OBP-801/LY294002 co-treatment. Additionally, OBP-801 was significantly more effective than SAHA, another HDAC inhibitor, in the combination with LY294002 against 786-O cells. Taken together, these results strongly suggest the combination of OBP-801 and LY294002 to be a promising treatment for RCC.
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1. 

Rini BI, Campbell SC and Escudier B: Renal cell carcinoma. Lancet. 373:1119–1132. 2009. View Article : Google Scholar : PubMed/NCBI

2. 

Gupta K, Miller JD, Li JZ, Russell MW and Charbonneau C: Epidemiologic and socioeconomic burden of metastatic renal cell carcinoma (mRCC): a literature review. Cancer Treat Rev. 34:193–205. 2008. View Article : Google Scholar : PubMed/NCBI

3. 

Kanno T, Kamba T, Yamasaki T, et al: JunB promotes cell invasion and angiogenesis in VHL-defective renal cell carcinoma. Oncogene. 31:3098–3110. 2012. View Article : Google Scholar : PubMed/NCBI

4. 

Mahalingam D, Medina EC, Esquivel JA II, et al: Vorinostat enhances the activity of temsirolimus in renal cell carcinoma through suppression of survivin levels. Clin Cancer Res. 16:141–153. 2010. View Article : Google Scholar : PubMed/NCBI

5. 

Carew JS, Esquivel JA II, Espitia CM, et al: ELR510444 inhibits tumor growth and angiogenesis by abrogating HIF activity and disrupting microtubules in renal cell carcinoma. PloS One. 7:e311202012. View Article : Google Scholar : PubMed/NCBI

6. 

Sosman JA, Puzanov I and Atkins MB: Opportunities and obstacles to combination targeted therapy in renal cell cancer. Clin Cancer Res. 13:S764–S769. 2007. View Article : Google Scholar : PubMed/NCBI

7. 

Marks PA, Richon VM and Rifkind RA: Histone deacetylase inhibitors: inducers of differentiation or apoptosis of transformed cells. J Natl Cancer Inst. 92:1210–1216. 2000. View Article : Google Scholar : PubMed/NCBI

8. 

Koyama M, Izutani Y, Goda AE, et al: Histone deacetylase inhibitors and 15-deoxy-Delta12,14-prostaglandin J2 synergistically induce apoptosis. Clin Cancer Res. 16:2320–2332. 2010. View Article : Google Scholar : PubMed/NCBI

9. 

Shindoh N, Mori M, Terada Y, et al: YM753, a novel histone deacetylase inhibitor, exhibits antitumor activity with selective, sustained accumulation of acetylated histones in tumors in the WiDr xenograft model. Int J Oncol. 32:545–555. 2008.

10. 

Luo J, Manning BD and Cantley LC: Targeting the PI3K-Akt pathway in human cancer: rationale and promise. Cancer Cell. 4:257–262. 2003. View Article : Google Scholar : PubMed/NCBI

11. 

Sourbier C, Lindner V, Lang H, et al: The phosphoinositide 3-kinase/Akt pathway: a new target in human renal cell carcinoma therapy. Cancer Res. 66:5130–5142. 2006. View Article : Google Scholar : PubMed/NCBI

12. 

Brognard J, Clark AS, Ni Y and Dennis PA: Akt/protein kinase B is constitutively active in non-small cell lung cancer cells and promotes cellular survival and resistance to chemotherapy and radiation. Cancer Res. 61:3986–3997. 2001.PubMed/NCBI

13. 

Kulik G, Carson JP, Vomastek T, et al: Tumor necrosis factor alpha induces BID cleavage and bypasses antiapoptotic signals in prostate cancer LNCaP cells. Cancer Res. 61:2713–2719. 2001.PubMed/NCBI

14. 

Izuishi K, Kato K, Ogura T, Kinoshita T and Esumi H: Remarkable tolerance of tumor cells to nutrient deprivation: possible new biochemical target for cancer therapy. Cancer Res. 60:6201–6207. 2000.PubMed/NCBI

15. 

Lee CM, Fuhrman CB, Planelles V, et al: Phosphatidylinositol 3-kinase inhibition by LY294002 radiosensitizes human cervical cancer cell lines. Clin Cancer Res. 12:250–256. 2006. View Article : Google Scholar : PubMed/NCBI

16. 

Zhou C, Qiu L, Sun Y, et al: Inhibition of EGFR/PI3K/AKT cell survival pathway promotes TSA’s effect on cell death and migration in human ovarian cancer cells. Int J Oncol. 29:269–278. 2006.PubMed/NCBI

17. 

Wang Q, Li N, Wang X, Kim MM and Evers BM: Augmentation of sodium butyrate-induced apoptosis by phosphatidylinositol 3′-kinase inhibition in the KM20 human colon cancer cell line. Clin Cancer Res. 8:1940–1947. 2002.

18. 

Park JK, Cho CH, Ramachandran S, et al: Augmentation of sodium butyrate-induced apoptosis by phosphatidylinositol 3-kinase inhibition in the human cervical cancer cell-line. Cancer Res Treat. 38:112–117. 2006. View Article : Google Scholar : PubMed/NCBI

19. 

Ozaki K, Kosugi M, Baba N, et al: Blockade of the ERK or PI3K-Akt signaling pathway enhances the cytotoxicity of histone deacetylase inhibitors in tumor cells resistant to gefitinib or imatinib. Biochem Biophys Res Commun. 391:1610–1615. 2010. View Article : Google Scholar : PubMed/NCBI

20. 

Wozniak MB, Villuendas R, Bischoff JR, et al: Vorinostat interferes with the signaling transduction pathway of T-cell receptor and synergizes with phosphoinositide-3 kinase inhibitors in cutaneous T-cell lymphoma. Haematologica. 95:613–621. 2010. View Article : Google Scholar : PubMed/NCBI

21. 

Rahmani M, Yu C, Reese E, et al: Inhibition of PI-3 kinase sensitizes human leukemic cells to histone deacetylase inhibitor-mediated apoptosis through p44/42 MAP kinase inactivation and abrogation of p21(CIP1/WAF1) induction rather than AKT inhibition. Oncogene. 22:6231–6242. 2003. View Article : Google Scholar

22. 

Nakata S, Yoshida T, Horinaka M, Shiraishi T, Wakada M and Sakai T: Histone deacetylase inhibitors upregulate death receptor 5/TRAIL-R2 and sensitize apoptosis induced by TRAIL/APO2-L in human malignant tumor cells. Oncogene. 23:6261–6271. 2004. View Article : Google Scholar

23. 

Carew JS, Giles FJ and Nawrocki ST: Histone deacetylase inhibitors: mechanisms of cell death and promise in combination cancer therapy. Cancer Lett. 269:7–17. 2008. View Article : Google Scholar : PubMed/NCBI

24. 

Bots M and Johnstone RW: Rational combinations using HDAC inhibitors. Clin Cancer Res. 15:3970–3977. 2009. View Article : Google Scholar : PubMed/NCBI

25. 

Ramaswamy B, Fiskus W, Cohen B, et al: Phase I–II study of vorinostat plus paclitaxel and bevacizumab in metastatic breast cancer: evidence for vorinostat-induced tubulin acetylation and Hsp90 inhibition in vivo. Breast Cancer Res Treat. 132:1063–1072. 2012.

26. 

Rathkopf D, Wong BY, Ross RW, et al: A phase I study of oral panobinostat alone and in combination with docetaxel in patients with castration-resistant prostate cancer. Cancer Chemother Pharmacol. 66:181–189. 2010. View Article : Google Scholar : PubMed/NCBI

27. 

Chinnaiyan P, Chowdhary S, Potthast L, et al: Phase I trial of vorinostat combined with bevacizumab and CPT-11 in recurrent glioblastoma. Neurooncology. 14:93–100. 2012.PubMed/NCBI

28. 

Fritzsche FR, Weichert W, Roske A, et al: Class I histone deacetylases 1, 2 and 3 are highly expressed in renal cell cancer. BMC Cancer. 8:3812008. View Article : Google Scholar : PubMed/NCBI

29. 

Hudes GR: Targeting mTOR in renal cell carcinoma. Cancer. 115:2313–2320. 2009. View Article : Google Scholar : PubMed/NCBI

30. 

Altieri DC: Survivin, cancer networks and pathway-directed drug discovery. Nat Revi Cancer. 8:61–70. 2008. View Article : Google Scholar : PubMed/NCBI

31. 

Mita AC, Mita MM, Nawrocki ST and Giles FJ: Survivin: key regulator of mitosis and apoptosis and novel target for cancer therapeutics. Clin Cancer Res. 14:5000–5005. 2008. View Article : Google Scholar : PubMed/NCBI

32. 

Krambeck AE, Dong H, Thompson RH, et al: Survivin and b7-h1 are collaborative predictors of survival and represent potential therapeutic targets for patients with renal cell carcinoma. Clin Cancer Res. 13:1749–1756. 2007. View Article : Google Scholar : PubMed/NCBI

33. 

Taniguchi H, Horinaka M, Yoshida T, et al: Targeting the Glyoxalase pathway enhances TRAIL efficacy in cancer cells by downregulating the expression of antiapoptotic molecules. Mol Cancer Ther. 11:2294–2300. 2012. View Article : Google Scholar : PubMed/NCBI

34. 

Zhu L, Fukuda S, Cordis G, Das DK and Maulik N: Anti-apoptotic protein survivin plays a significant role in tubular morphogenesis of human coronary arteriolar endothelial cells by hypoxic preconditioning. FEBS Lett. 508:369–374. 2001. View Article : Google Scholar

35. 

Stehlik C, de Martin R, Kumabashiri I, Schmid JA, Binder BR and Lipp J: Nuclear factor (NF)-kappaB-regulated X-chromosome-linked iap gene expression protects endothelial cells from tumor necrosis factor alpha-induced apoptosis. J Exp Med. 188:211–216. 1998. View Article : Google Scholar

36. 

Qu Y, Wang J, Ray PS, et al: Thioredoxin-like 2 regulates human cancer cell growth and metastasis via redox homeostasis and NF-kappaB signaling. J Clin Invest. 121:212–225. 2011. View Article : Google Scholar : PubMed/NCBI

37. 

Yoshioka T, Yogosawa S, Yamada T, Kitawaki J and Sakai T: Combination of a novel HDAC inhibitor OBP-801/YM753 and a PI3K inhibitor LY294002 synergistically induces apoptosis in human endometrial carcinoma cells due to increase of Bim with accumulation of ROS. Gynecol Oncol. 129:425–432. 2013. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
Spandidos Publications style
Yamada T, Horinaka M, Shinnoh M, Yoshioka T, Miki T and Sakai T: A novel HDAC inhibitor OBP-801 and a PI3K inhibitor LY294002 synergistically induce apoptosis via the suppression of survivin and XIAP in renal cell carcinoma. Int J Oncol 43: 1080-1086, 2013.
APA
Yamada, T., Horinaka, M., Shinnoh, M., Yoshioka, T., Miki, T., & Sakai, T. (2013). A novel HDAC inhibitor OBP-801 and a PI3K inhibitor LY294002 synergistically induce apoptosis via the suppression of survivin and XIAP in renal cell carcinoma. International Journal of Oncology, 43, 1080-1086. https://doi.org/10.3892/ijo.2013.2042
MLA
Yamada, T., Horinaka, M., Shinnoh, M., Yoshioka, T., Miki, T., Sakai, T."A novel HDAC inhibitor OBP-801 and a PI3K inhibitor LY294002 synergistically induce apoptosis via the suppression of survivin and XIAP in renal cell carcinoma". International Journal of Oncology 43.4 (2013): 1080-1086.
Chicago
Yamada, T., Horinaka, M., Shinnoh, M., Yoshioka, T., Miki, T., Sakai, T."A novel HDAC inhibitor OBP-801 and a PI3K inhibitor LY294002 synergistically induce apoptosis via the suppression of survivin and XIAP in renal cell carcinoma". International Journal of Oncology 43, no. 4 (2013): 1080-1086. https://doi.org/10.3892/ijo.2013.2042
Copy and paste a formatted citation
x
Spandidos Publications style
Yamada T, Horinaka M, Shinnoh M, Yoshioka T, Miki T and Sakai T: A novel HDAC inhibitor OBP-801 and a PI3K inhibitor LY294002 synergistically induce apoptosis via the suppression of survivin and XIAP in renal cell carcinoma. Int J Oncol 43: 1080-1086, 2013.
APA
Yamada, T., Horinaka, M., Shinnoh, M., Yoshioka, T., Miki, T., & Sakai, T. (2013). A novel HDAC inhibitor OBP-801 and a PI3K inhibitor LY294002 synergistically induce apoptosis via the suppression of survivin and XIAP in renal cell carcinoma. International Journal of Oncology, 43, 1080-1086. https://doi.org/10.3892/ijo.2013.2042
MLA
Yamada, T., Horinaka, M., Shinnoh, M., Yoshioka, T., Miki, T., Sakai, T."A novel HDAC inhibitor OBP-801 and a PI3K inhibitor LY294002 synergistically induce apoptosis via the suppression of survivin and XIAP in renal cell carcinoma". International Journal of Oncology 43.4 (2013): 1080-1086.
Chicago
Yamada, T., Horinaka, M., Shinnoh, M., Yoshioka, T., Miki, T., Sakai, T."A novel HDAC inhibitor OBP-801 and a PI3K inhibitor LY294002 synergistically induce apoptosis via the suppression of survivin and XIAP in renal cell carcinoma". International Journal of Oncology 43, no. 4 (2013): 1080-1086. https://doi.org/10.3892/ijo.2013.2042
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