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Title: Suprafenacine, an indazole-hydrazide agent, targets cancer cells through microtubule destabilization
Authors: Choi, Bo-Hwa
Chattopadhaya, Souvik
Feng, Lin
Nguyen, Quoc Toan
Lim, Chuan Bian
Harikishore, Amaravadhi
Nanga, Ravi Prakash Reddy
Bharatham, Nagakumar
Zhao, Yan
Yoon, Ho Sup
Thanh, Le Nguyen
Liu, Xuewei
Keywords: DRNTU::Science::Biological sciences::Human anatomy and physiology
Issue Date: 2014
Source: Choi, B. H., Chattopadhaya, S., Feng, L., Thanh, L. N., Lim, C. B., Nguyen, Q. T., Harikishore, A., Nanga, R. P. R., Bharatham, N., Zhao, Y., Yoon, H. S., & Liu, X. (2014). Suprafenacine, an indazole-hydrazide agent, targets cancer cells through microtubule destabilization. PLoS One, 9(10), e110955-.
Series/Report no.: PLoS One
Abstract: Microtubules are a highly validated target in cancer therapy. However, the clinical development of tubulin binding agents (TBA) has been hampered by toxicity and chemoresistance issues and has necessitated the search for new TBAs. Here, we report the identification of a novel cell permeable, tubulin-destabilizing molecule - 4,5,6,7-tetrahydro-1H-indazole-3-carboxy​licacid [1p-tolyl-meth-(E)-ylidene]-hydrazide (termed as Suprafenacine, SRF). SRF, identified by in silico screening of annotated chemical libraries, was shown to bind microtubules at the colchicine-binding site and inhibit polymerization. This led to G2/M cell cycle arrest and cell death via a mitochondria-mediated apoptotic pathway. Cell death was preceded by loss of mitochondrial membrane potential, JNK - mediated phosphorylation of Bcl-2 and Bad, and activation of caspase-3. Intriguingly, SRF was found to selectively inhibit cancer cell proliferation and was effective against drug-resistant cancer cells by virtue of its ability to bypass the multidrug resistance transporter P-glycoprotein. Taken together, our results suggest that SRF has potential as a chemotherapeutic agent for cancer treatment and provides an alternate scaffold for the development of improved anti-cancer agents.
ISSN: 1932-6203
DOI: 10.1371/journal.pone.0110955
Schools: School of Biological Sciences 
School of Physical and Mathematical Sciences 
Rights: © 2014 Choi et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:SPMS Journal Articles

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