Abstract 2757: TAS-106, a newly synthesized RNA polymerase inhibitor, combined with cisplatin exhibits potent synergistic growth-inhibitory effect via Vaults dysfunction
Authors: Hiroto Fukushima, Tetsuya Abe, Akihiro Tsujimoto, Rumi Kawabata, Kazuki Sakamoto, Shinji Oie
Journal: Cancer Research (2012)

Abstract TAS-106, 3′-C-ethynylcytidine, is a novel nucleoside analog that inhibits RNA polymerases I, II and III, and has been reported to exert potent antitumor activities in preclinical studies. We tried to investigate antitumor activity of TAS-106 combined with cisplatin (CDDP) in CDDP resistant Head and Neck cancer cell line KB/CDDP cells and clarify the underlying mechanism of this combination therapy. Initially, we evaluated the growth-inhibitory activities of various antitumor drugs in both KB/CDDP cells and its parent cell line KB cells, and found that KB/CDDP cells, interestingly, displayed resistance not only to CDDP but also to adriamycin, paclitaxel and so on. But, TAS-106 showed similar antitumor effect on both KB and KB/CDDP cells. We assessed the synergism of TAS-106 and CDDP on KB/CDDP cells by an isobologram analysis method, and revealed the combination showed a potent synergistic growth inhibitory effect on KB/CDDP cells. We next focused on the intracellular ribonucleoprotein particles Vaults that play a pivotal role in multi-drug resistance by transporting drugs away from their intracellular targets. Vaults are composed of a major vault protein (MVP), two minor vault proteins, and small untranslated vault RNA (vRNA). Especially vRNA is thought to be an important component because it interacts with anticancer drugs and also transcribed by RNA polymerase III that is the target of TAS-106. To examine whether Vaults contribute to the resistance to CDDP in KB/CDDP cells, we analyzed the effect of MVP-silencing by siRNA on the sensitivity to CDDP. MVP knock-down significantly sensitized the cells to CDDP, and reduced IC50 value about 16-fold. Next, we checked the effect of TAS-106 on vRNA expression, and found that vRNA expression decreased to approximately 50% after 2 hr exposure of TAS-106, whereas, mRNA expression levels weren't affected. Moreover, we found that TAS-106 showed &amp;gt;2-fold reduction of vRNA in xenograft tumors in nude mice after 6 hr drug exposure. These data strongly suggest that TAS-106 be a potent inhibitor of Vaults function and reverse the CDDP resistance associated with Vaults. This is the first report showing that small molecules with RNA polymerase inhibition, such as TAS-106, exerted not only a potent antitumor activity by itself but also induced Vaults dysfunction by inhibiting the synthesis of vRNA, and subsequently reversed the CDDP resistance. CDDP is still now one of the key drugs of the combination chemotherapy for various kinds of cancer including Head and Neck, lung and ovarian cancer. However, almost all patients who first show good response to platinum based chemotherapy become refractory to this therapy. A combination therapy with CDDP and TAS-106 might provide great benefit for patients whose tumor has an intrinsic resistance to CDDP or acquired resistance after CDDP treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2757. doi:1538-7445.AM2012-2757