Antimitotic sulfonamides inhibit microtubule assembly dynamics and cancer cell proliferation.
Several sulfonamides have antitumor activities and are currently undergoing clinical evaluation for the treatment of cancer. In this study, we have elucidated the antiproliferative mechanism of action of five indole sulfonamides. The indole sulfonamides inhibited the polymerization of microtubule protein into microtubules in vitro. In addition, three representative derivatives, ER-68378 (2), ER-68384 (4) and ER-68394 (5), suppressed the dynamic instability behavior at the plus ends of individual steady-state microtubules in vitro. The analogues inhibited HeLa cell proliferation with half-maximal inhibitory concentrations in the range of 6-17 microM. The compounds blocked cell cycle progression at mitosis. At their lowest effective antimitotic concentrations, they depolymerized the spindle microtubules and disorganized the chromosomes but did not affect the microtubules in interphase cells. However, at relatively high concentrations, interphase microtubules were also depolymerized by these sulfonamides. Furthermore, all five compounds were found to induce apoptosis in the cells in association with the phosphorylation of bcl-2. The results suggest that the indole sulfonamides inhibit cell proliferation at mitosis by perturbing the assembly dynamics of spindle microtubules and that they can kill cancer cells by inducing apoptosis through the bcl-2-dependent pathway.
Mohan
Renu
R
School of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai 400076, India.
Banerjee
Mithu
M
Ray
Anasuya
A
Manna
Tapas
T
Wilson
Leslie
L
Owa
Takashi
T
Bhattacharyya
Bhabatarak
B
Panda
Dulal
D
D000627:Aminophenols / Q000494:pharmacology; D050256:Antimitotic Agents / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007399:Interphase / Q000187:drug effects; D008870:Microtubules / Q000187:drug effects* / Q000502:physiology; D008938:Mitosis / Q000187:drug effects*; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D008941:Spindle Apparatus / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology*; D000096926:Benzenesulfonamides
D000627:Aminophenols; D050256:Antimitotic Agents; D000970:Antineoplastic Agents; D007211:Indoles; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; C079199:E 7010; D000096926:Benzenesulfonamides