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

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 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 G(2)M 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.

• Authors: Sunjoo Ahn, Dong Jin Hwang, Christina M Barrett, Jun Yang, Charles B Duke 3rd, Duane D Miller, James T Dalton
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 67 Issue 2 Pg. 293-304 (Feb 2011) ISSN: 1432-0843 [Electronic] Germany
• PMID: 20383708 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• (3-(1H-indol-2-yl)phenyl)(1H-indol-2-yl)methanone
• ABCG2 protein, human
• ATP Binding Cassette Transporter, Subfamily B, Member 1
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters
• Indoles
• Multidrug Resistance-Associated Proteins
• Neoplasm Proteins
• Tubulin
• Tubulin Modulators
• Vinblastine
• Podophyllotoxin

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (metabolism)
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters (metabolism)
• Animals
• Apoptosis (drug effects)
• Binding Sites
• Binding, Competitive
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Humans
• Indoles (chemistry, metabolism, pharmacology, therapeutic use, toxicity)
• Inhibitory Concentration 50
• Male
• Maximum Tolerated Dose
• Mice
• Mice, Inbred ICR
• Mice, Nude
• Microtubules (drug effects)
• Molecular Structure
• Multidrug Resistance-Associated Proteins (metabolism)
• Neoplasm Proteins (metabolism)
• Podophyllotoxin (metabolism)
• Prostatic Neoplasms (drug therapy, pathology)
• Survival Rate
• Tubulin (metabolism)
• Tubulin Modulators (chemistry, metabolism, pharmacology, therapeutic use, toxicity)
• Vinblastine (metabolism)
• Xenograft Model Antitumor Assays