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

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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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Abbreviations

MRP:

Multidrug resistance-associated proteins

BCRP:

Breast cancer resistance protein

MDR:

Multidrug resistance

ABC:

ATP-binding cassette

SRB:

Sulforhodamine B

MTT:

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

FACS:

Fluorescence-activated cell sorting

MTD:

Maximally tolerated dose

T/C:

Treated over control tumor volume ratio × 100%

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Acknowledgments

These studies were supported by grant #PC060380 from the Department of Defense Prostate Cancer Research Program of the US Army Medical Research and Materiel Command.

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Authors and Affiliations

  1. Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, OH, USA

    Sunjoo Ahn, Jun Yang & James T. Dalton

  2. Preclinical Research and Development, GTx, Inc., 3 North Dunlap Street, Memphis, TN, 38163, USA

    Sunjoo Ahn, Dong Jin Hwang, Christina M. Barrett, Duane D. Miller & James T. Dalton

  3. Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee, Memphis, TN, USA

    Charles B. Duke III & Duane D. Miller

Authors
  1. Sunjoo Ahn
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  2. Dong Jin Hwang
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  3. Christina M. Barrett
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  4. Jun Yang
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Correspondence to James T. Dalton.

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Ahn, S., Hwang, D.J., Barrett, C.M. et al. A novel bis-indole destabilizes microtubules and displays potent in vitro and in vivo antitumor activity in prostate cancer. Cancer Chemother Pharmacol 67, 293–304 (2011). https://doi.org/10.1007/s00280-010-1319-8

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  • DOI: https://doi.org/10.1007/s00280-010-1319-8

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