A novel bis-indole destabilizes microtubules and displays potent in vitro and in vivo antitumor activity in prostate cancer.
OBJECTIVE
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.
Ahn
Sunjoo
S
Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, OH, USA.
Hwang
Dong Jin
DJ
Barrett
Christina M
CM
Yang
Jun
J
Duke
Charles B
CB
Miller
Duane D
DD
Dalton
James T
JT
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D001667:Binding, Competitive; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use* / Q000633:toxicity; D020128:Inhibitory Concentration 50; D008297:Male; D020714:Maximum Tolerated Dose; D051379:Mice; D008813:Mice, Inbred ICR; D008819:Mice, Nude; D008870:Microtubules / Q000187:drug effects*; D015394:Molecular Structure; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D011034:Podophyllotoxin / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D015996:Survival Rate; D014404:Tubulin / Q000378:metabolism; D050257:Tubulin Modulators / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use* / Q000633:toxicity; D014747:Vinblastine / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D007211:Indoles; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D011034:Podophyllotoxin; D014404:Tubulin; D050257:Tubulin Modulators; D014747:Vinblastine; C557277:(3-(1H-indol-2-yl)phenyl)(1H-indol-2-yl)methanone; C116614:ABCG2 protein, human