Therapeutic efficacy of a novel betaIII/betaIV-tubulin inhibitor (VERU-111) in pancreatic cancer.

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Kashyap VK, Wang Q, Setua S, Nagesh PKB, Chauhan N, Kumari S, Chowdhury P, Miller DD, Yallapu MM, Li W, Jaggi M, Hafeez BB, Chauhan SC

Therapeutic efficacy of a novel betaIII/betaIV-tubulin inhibitor (VERU-111) in pancreatic cancer.

J Exp Clin Cancer Res. 2019 Jan 23;38(1):29. doi: 10.1186/s13046-018-1009-7.

PubMed ID
30674344 [ View in PubMed
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Abstract

BACKGROUND: The management of pancreatic cancer (PanCa) is exceptionally difficult due to poor response to available therapeutic modalities. Tubulins play a major role in cell dynamics, thus are important molecular targets for cancer therapy. Among various tubulins, betaIII and betaIV-tubulin isoforms have been primarily implicated in PanCa progression, metastasis and chemo-resistance. However, specific inhibitors of these isoforms that have potent anti-cancer activity with low toxicity are not readily available. METHODS: We determined anti-cancer molecular mechanisms and therapeutic efficacy of a novel small molecule inhibitor (VERU-111) using in vitro (MTS, wound healing, Boyden chamber and real-time xCELLigence assays) and in vivo (xenograft studies) models of PanCa. The effects of VERU-111 treatment on the expression of beta-tubulin isoforms, apoptosis, cancer markers and microRNAs were determined by Western blot, immunohistochemistry (IHC), confocal microscopy, qRT-PCR and in situ hybridization (ISH) analyses. RESULTS: We have identified a novel small molecule inhibitor (VERU-111), which preferentially represses clinically important, betaIII and betaIV tubulin isoforms via restoring the expression of miR-200c. As a result, VERU-111 efficiently inhibited tumorigenic and metastatic characteristics of PanCa cells. VERU-111 arrested the cell cycle in the G2/M phase and induced apoptosis in PanCa cell lines via modulation of cell cycle regulatory (Cdc2, Cdc25c, and Cyclin B1) and apoptosis - associated (Bax, Bad, Bcl-2, and Bcl-xl) proteins. VERU-111 treatment also inhibited tumor growth (P < 0.01) in a PanCa xenograft mouse model. CONCLUSIONS: This study has identified an inhibitor of betaIII/betaIV tubulins, which appears to have excellent potential as monotherapy or in combination with conventional therapeutic regimens for PanCa treatment.

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