An Indole-Chalcone Inhibits Multidrug-Resistant Cancer Cell Growth by Targeting Microtubules

Hui Cong, Xinghua Zhao, Brian T Castle, Emily J. Pomeroy, Bo Zhou, John Lee, Yi Wang, Tengfei Bian, Zhenyuan Miao, Wannian Zhang, Yuk Y Sham, David J Odde, Craig E Eckfeldt, Chengguo Xing, Chunlin Zhuang

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Multidrug resistance and toxic side effects are the major challenges in cancer treatment with microtubule-targeting agents (MTAs), and thus, there is an urgent clinical need for new therapies. Chalcone, a common simple scaffold found in many natural products, is widely used as a privileged structure in medicinal chemistry. We have previously validated tubulin as the anticancer target for chalcone derivatives. In this study, an α-methyl-substituted indole-chalcone (FC77) was synthesized and found to exhibit an excellent cytotoxicity against the NCI-60 cell lines (average concentration causing 50% growth inhibition = 6 nM). More importantly, several multidrug-resistant cancer cell lines showed no resistance to FC77, and the compound demonstrated good selective toxicity against cancer cells versus normal CD34 + blood progenitor cells. A further mechanistic study demonstrated that FC77 could arrest cells that relate to the binding to tubulin and inhibit the microtubule dynamics. The National Cancer Institute COMPARE analysis and molecular modeling indicated that FC77 had a mechanism of action similar to that of colchicine. Overall, our data demonstrate that this indole-chalcone represents a novel MTA template for further development of potential drug candidates for the treatment of multidrug-resistant cancers.

Original languageEnglish (US)
Pages (from-to)3892-3900
Number of pages9
JournalMolecular Pharmaceutics
Volume15
Issue number9
DOIs
StatePublished - Sep 4 2018

Fingerprint

Chalcone
Microtubules
Tubulin
Growth
Neoplasms
Cell Line
National Cancer Institute (U.S.)
Pharmaceutical Chemistry
Poisons
Colchicine
Multiple Drug Resistance
Biological Products
Blood Cells
Stem Cells
indole
Pharmaceutical Preparations

Keywords

  • cancer
  • indole-chalcone
  • microtubule-targeting agent
  • multidrug resistance

Cite this

An Indole-Chalcone Inhibits Multidrug-Resistant Cancer Cell Growth by Targeting Microtubules. / Cong, Hui; Zhao, Xinghua; Castle, Brian T; Pomeroy, Emily J.; Zhou, Bo; Lee, John; Wang, Yi; Bian, Tengfei; Miao, Zhenyuan; Zhang, Wannian; Sham, Yuk Y; Odde, David J; Eckfeldt, Craig E; Xing, Chengguo; Zhuang, Chunlin.

In: Molecular Pharmaceutics, Vol. 15, No. 9, 04.09.2018, p. 3892-3900.

Research output: Contribution to journalArticle

Cong, H, Zhao, X, Castle, BT, Pomeroy, EJ, Zhou, B, Lee, J, Wang, Y, Bian, T, Miao, Z, Zhang, W, Sham, YY, Odde, DJ, Eckfeldt, CE, Xing, C & Zhuang, C 2018, 'An Indole-Chalcone Inhibits Multidrug-Resistant Cancer Cell Growth by Targeting Microtubules', Molecular Pharmaceutics, vol. 15, no. 9, pp. 3892-3900. https://doi.org/10.1021/acs.molpharmaceut.8b00359
Cong, Hui ; Zhao, Xinghua ; Castle, Brian T ; Pomeroy, Emily J. ; Zhou, Bo ; Lee, John ; Wang, Yi ; Bian, Tengfei ; Miao, Zhenyuan ; Zhang, Wannian ; Sham, Yuk Y ; Odde, David J ; Eckfeldt, Craig E ; Xing, Chengguo ; Zhuang, Chunlin. / An Indole-Chalcone Inhibits Multidrug-Resistant Cancer Cell Growth by Targeting Microtubules. In: Molecular Pharmaceutics. 2018 ; Vol. 15, No. 9. pp. 3892-3900.
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