Abstract 3216: Attenuation of pancreatic tumor growth by a small molecule tubulin inhibitor
Authors: Kashyap Vivek K. , Hafeez Bilal B. , Wang Qinghui , Setua Saini , Massey Andrew , Ganju Aditya , Yallapu Murali M. , Miller Duane D. , Li Wei , Jaggi Meena , Chauhan Subhash C. 
Published: July 2017

Introduction: Pancreatic cancer (PanCa) is one of the most fatal cancers and is ranked as the fourth common cause of cancer-related deaths among both men and women in the US. The management of PanCa is exceptionally difficult due to the extremely poor response to available chemotherapeutic drugs. Microtubules are dynamic structures composed of α-β-tubulin heterodimers that are essential in cell division and are important targets for several clinical drugs (paclitaxel, docetaxel and vinblastine). However, clinical use of these tubulin-targeting drugs have toxicity and drug resistance issues in cancer patients. Thus, identification of more potent non-toxic inhibitors of β-tubulin is urgently required for cancer therapy purposes. In this study, we have identified a synthetic compound (ABI-231) which is a potent inhibitor of β-tubulin and evaluated its therapeutic efficacy against PanCa in vitro, and in vivo model systems.

Methods: ABI-231 ((2-(1H-indol-3-yl)-1H-imidazol-4-yl) (3, 4, 5-trimethoxyphenyl)) - methanone was synthesized and characterized in our department. Effect of ABI-231 on proliferation, migration and invasion of human PanCa cells (ASPC1, HPAFII, and PANC1) was performed by in vitro functional assays (MTS, wound healing, and Boyden chamber migrations). Effect of ABI-231 on the expression of β-tubulin isoforms was determined and compared with other clinical inhibitors of β-tubulin by Western blot, and qRT-PCR. Moreover, the effect of ABI-231 on the expression of β-tubulin III in PanCa cells was determined by confocal microscopy. Therapeutic efficacy of ABI-231 against PanCa was evaluated in an ectopic xenograft mouse model.

Results: ABI-231 treatment inhibited cell proliferation, invasion, migration and colony formation abilities of PanCa cells in a dose-dependent manner (1-100 nM) compared to vehicle treated group. Aberrant expression of β-tubulin III is involved in aggressiveness and drug resistance of various type of cancers including PanCa. ABI-231 effectively inhibited the protein levels and mRNA expression of total β-tubulin (TBB), TBB1, TBB2c, TBB3 and TBB4 in PanCa cells via destabilization. Our confocal microscopy results further showed inhibition of β-tubulin in ABI-231 treated PanCa cells. Upregulation of micro RNA 200c (miR-200c) has been shown to inhibit the expression of β-tubulin III in cancer cells. ABI-231 treatment of PanCa cells showed significant (p&lt;0.01) induction of miR-200c as determined by qRT-PCR. ABI-231 administration (intra-tumoral; 50μg/mouse), three times/week significantly (p&lt;0.01) inhibited the growth of ASPC1 cells derived xenograft tumors in athymic nude mice.

Conclusion: Taken together, our results suggest that ABI-231 is a potent β-tubulin inhibitor and chemotherapeutic agent which could be used for the treatment of pancreatic cancer.

Citation Format: Vivek K. Kashyap, Bilal B. Hafeez, Qinghui Wang, Saini Setua, Andrew Massey, Aditya Ganju, Murali M. Yallapu, Duane D. Miller, Wei Li, Meena Jaggi, Subhash C. Chauhan. Attenuation of pancreatic tumor growth by a small molecule tubulin inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3216. doi:10.1158/1538-7445.AM2017-3216