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01.02.2011 | Original Article

A novel bis-indole destabilizes microtubules and displays potent in vitro and in vivo antitumor activity in prostate cancer

verfasst von: Sunjoo Ahn, Dong Jin Hwang, Christina M. Barrett, Jun Yang, Charles B. Duke III, Duane D. Miller, James T. Dalton

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 2/2011

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Abstract

Purpose

Microtubules are one of the most useful subcellular targets in chemotherapy. We identified a novel indole, (3-(1H-indol-2-yl)phenyl)(1H-indol-2-yl)methanone (15), that inhibits tubulin action and exhibits potent antitumor activity in various preclinical models.

Methods

In vitro cancer cell growth inhibition was measured by SRB or MTT assay in human cancer cell lines. Apoptosis induced by 15 was examined in LNCaP and PC-3 cells. Effects of 15 on cell cycle distribution and tubulin were investigated via in vitro models. In vivo toxicity and xenograft efficacy studies were conducted in mice.

Results

Indole 15 inhibited the in vitro growth of a number of human cancer cell lines, including drug-resistant cell lines that over-express P-glycoprotein, multidrug resistance-associated proteins, and breast cancer resistance protein with IC₅₀ values in the range of 34–162 nM. Nanomolar concentrations of the compound caused down-regulation of bcl-2, induced PARP cleavage, and induced apoptosis in both LNCaP and PC-3 prostate cancer cells, as confirmed by anti-histone ELISA and DNA laddering. In vitro studies revealed that the compound inhibited polymerization of purified tubulin and induced a strong and concentration-dependent G₂M arrest in PC-3 cells. In vivo studies in immunodeficient mice bearing PC-3 tumor xenografts showed that the compound effectively inhibited tumor growth.

Conclusions

The potent in vitro and in vivo antitumor activities of this novel indole suggest that drugs with this novel chemical scaffold might be developed for treatment of drug-resistant prostate cancer.

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Titel: A novel bis-indole destabilizes microtubules and displays potent in vitro and in vivo antitumor activity in prostate cancer
verfasst von: Sunjoo Ahn
Dong Jin Hwang
Christina M. Barrett
Jun Yang
Charles B. Duke III
Duane D. Miller
James T. Dalton
Publikationsdatum: 01.02.2011
Verlag: Springer-Verlag
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 2/2011
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-010-1319-8

Springer Medizin

A novel bis-indole destabilizes microtubules and displays potent in vitro and in vivo antitumor activity in prostate cancer