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

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

Research output: Contribution to journalArticle

15 Citations (Scopus)

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 IC 50 values in the range of 34-162 nM. Nanomolar concentrations of the compound caused downregulation 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 G 2M 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.

Original languageEnglish (US)
Pages (from-to)293-304
Number of pages12
JournalCancer Chemotherapy and Pharmacology
Volume67
Issue number2
DOIs
StatePublished - Feb 1 2011

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Microtubules
Prostatic Neoplasms
Display devices
Cells
Tubulin
Neoplasms
Heterografts
Cell Line
Tumors
Bearings (structural)
Growth
Pharmaceutical Preparations
Apoptosis
Multidrug Resistance-Associated Proteins
Chemotherapy
Cell growth
P-Glycoprotein
Scaffolds
Polymerization
Histones

All Science Journal Classification (ASJC) codes

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

Cite this

A novel bis-indole destabilizes Microtubules and displays potent in vitro and in vivo antitumor activity in prostate cancer. / Ahn, Sunjoo; Hwang, Dong Jin; Barrett, Christina M.; Yang, Jun; Duke, Charles B.; Miller, Duane; Dalton, James T.

In: Cancer Chemotherapy and Pharmacology, Vol. 67, No. 2, 01.02.2011, p. 293-304.

Research output: Contribution to journalArticle

Ahn, Sunjoo ; Hwang, Dong Jin ; Barrett, Christina M. ; Yang, Jun ; Duke, Charles B. ; Miller, Duane ; Dalton, James T. / A novel bis-indole destabilizes Microtubules and displays potent in vitro and in vivo antitumor activity in prostate cancer. In: Cancer Chemotherapy and Pharmacology. 2011 ; Vol. 67, No. 2. pp. 293-304.
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