Therapeutic efficacy of a novel βiII/βIV-tubulin inhibitor (VERU-111) in pancreatic cancer

Vivek K. Kashyap, Qinghui Wang, Saini Setua, Prashanth K.B. Nagesh, Neeraj Chauhan, Sonam Kumari, Pallabita Chowdhury, Duane Miller, Murali Yallapu, Wei Li, Meena Jaggi, Bilal Hafeez, Subhash Chauhan

Research output: Contribution to journalArticle

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, βIII and βIV-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 β-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, βIII and βIV 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 βIII/βIV tubulins, which appears to have excellent potential as monotherapy or in combination with conventional therapeutic regimens for PanCa treatment.

Original languageEnglish (US)
Article number29
JournalJournal of Experimental and Clinical Cancer Research
Volume38
Issue number1
DOIs
StatePublished - Jan 23 2019

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Tubulin Modulators
Pancreatic Neoplasms
Tubulin
Protein Isoforms
Neoplasms
Apoptosis
Heterografts
Therapeutics
Cell Cycle
Cyclin B1
G2 Phase
MicroRNAs
Confocal Microscopy
Cell Division
Wound Healing
In Situ Hybridization
Western Blotting
Immunohistochemistry
Neoplasm Metastasis
Cell Line

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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Therapeutic efficacy of a novel βiII/βIV-tubulin inhibitor (VERU-111) in pancreatic cancer. / Kashyap, Vivek K.; Wang, Qinghui; Setua, Saini; Nagesh, Prashanth K.B.; Chauhan, Neeraj; Kumari, Sonam; Chowdhury, Pallabita; Miller, Duane; Yallapu, Murali; Li, Wei; Jaggi, Meena; Hafeez, Bilal; Chauhan, Subhash.

In: Journal of Experimental and Clinical Cancer Research, Vol. 38, No. 1, 29, 23.01.2019.

Research output: Contribution to journalArticle

Kashyap, Vivek K. ; Wang, Qinghui ; Setua, Saini ; Nagesh, Prashanth K.B. ; Chauhan, Neeraj ; Kumari, Sonam ; Chowdhury, Pallabita ; Miller, Duane ; Yallapu, Murali ; Li, Wei ; Jaggi, Meena ; Hafeez, Bilal ; Chauhan, Subhash. / Therapeutic efficacy of a novel βiII/βIV-tubulin inhibitor (VERU-111) in pancreatic cancer. In: Journal of Experimental and Clinical Cancer Research. 2019 ; Vol. 38, No. 1.
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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, βIII and βIV-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 β-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, βIII and βIV 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 βIII/βIV tubulins, which appears to have excellent potential as monotherapy or in combination with conventional therapeutic regimens for PanCa treatment.",
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AU - Kashyap, Vivek K.

AU - Wang, Qinghui

AU - Setua, Saini

AU - Nagesh, Prashanth K.B.

AU - Chauhan, Neeraj

AU - Kumari, Sonam

AU - Chowdhury, Pallabita

AU - Miller, Duane

AU - Yallapu, Murali

AU - Li, Wei

AU - Jaggi, Meena

AU - Hafeez, Bilal

AU - Chauhan, Subhash

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AB - 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, βIII and βIV-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 β-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, βIII and βIV 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 βIII/βIV tubulins, which appears to have excellent potential as monotherapy or in combination with conventional therapeutic regimens for PanCa treatment.

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