Unusual potentiation by vinca alkaloids of the cytostatic and cytocidal action of methyl-3,5-diiodo-4-(4'-methoxyphenoxy) benzoate (DIME) and its nonhydrolyzable ethanone analog (DIPE) on MDA-MB-231 human mammary cancer cells.
Drug interaction between DIME or DIPE ¿1-[3, 5-diiodo-4-(4'-methoxyphenoxy)-phenyl]-ethanone¿ with vincristine and vinblastine on the growth rate of MDA-MB-231 human mammary cancer cells was determined by the median effect kinetic method. Mutually exclusive cellular binding sites were identified kinetically and isobologram analyses showed potentiation. The combind effect of 0.75 MICROM DIME and 2 nM vincristine demonstrated a nearly type of mutual activation. It was shown that the nonhydrolyzable DIME derivative DIPE is equivalent to DIME, but because of its biological stability is a preferred drug candidate. Vinblastine-DIME cooperative action is similar to that of vincristine-DIME (or DIPE). Activation of caspase 3 by both DIME and vincristine is greatly potentiated when both drugs are added simultaneously in a given proportion. We propose that following a primary binding of DIME and vinca alkaloids to microtubules, an as yet unrecognized mutual activation of caspase 3 apoptotic path is initiated, explaining DNA fragmentation and cell death. A subpopulation of cancer cells, capable of slow growth at 1.5 microM DIME was identified. This cell type was also killed by the DIME-vincristine drug combination.
Kirsten
E
E
Octamer Inc. and Octamer Research Foundation, 2840 Eighth Street, Berkeley, CA 94710, USA.
Buki
K G
KG
Mendeleyev
J
J
Vidair
C A
CA
Kun
A
A
Kun
E
E
D000970:Antineoplastic Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000473:pathology*; D053148:Caspase 3; D020169:Caspases; D016923:Cell Death / Q000187:drug effects; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007462:Iodobenzenes / Q000494:pharmacology*; D007463:Iodobenzoates / Q000494:pharmacology*; D007700:Kinetics; D010647:Phenyl Ethers / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014747:Vinblastine / Q000494:pharmacology*; D014750:Vincristine / Q000494:pharmacology*
C113715:1-(3,5-diiodo-4-(4'-methoxyphenoxy)phenyl)ethanone; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D007462:Iodobenzenes; D007463:Iodobenzoates; D010647:Phenyl Ethers; C436733:methyl 3,5-diiodo-4-(4'-methoxyphenoxy)benzoate; D014750:Vincristine; D014747:Vinblastine; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases