Vinca alkaloid-induced tubulin spiral formation correlates with cytotoxicity in the leukemic L1210 cell line.
The ability of a class of C-20' modified vinca alkaloid congeners to induce tubulin spiral formation was investigated relative to their ability to inhibit microtubule assembly, their cytotoxicity against a leukemic cell line, L1210, and their measured and calculated partition coefficients. These studies were prompted by the observation that the energetics of vinca alkaloid-induced tubulin spiral polymers, or spiraling potential, is inversely related to their clinical dosage and are aimed at the long-term goal of developing the ability to predict the cytotoxic and antineoplastic properties of antimitotic drugs. We demonstrate here that vinca-induced tubulin-spiraling potential is significantly correlated with cytotoxicity against L1210 cells. This is consistent with the size of spirals formed being proportional to the relaxation time for polymer redistribution, the lifetime of cell retention, and effects on microtubule ends and dynamics. Spiraling potential also correlates with calculated but not measured partition coefficients. Surprisingly, spiraling potential does not correlate with the ability to inhibit microtubule formation with purified tubulin or microtubule protein. For the set of C-20' modified compounds studied, the largest inhibitory effects on spiraling potential and cytotoxicity are caused by multiple sites of halogen (-F, -Cl) substitution with the introduction of increased rigidity in the ring. This suggests the C-20' position interacts with a hydrogen bond acceptor or an electrophilic region on the protein that electrostatically disfavors halogen substitutions. These studies are discussed in terms of the cellular mode of action of antimitotic drugs, particularly the importance of microtubule dynamics during mitosis and the factors that regulate those dynamics.
Lobert
S
S
School of Nursing and Department of Biochemistry, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA. slobert@son.umsmed.edu
Fahy
J
J
Hill
B T
BT
Duflos
A
A
Etievant
C
C
Correia
J J
JJ
D000818:Animals; D001665:Binding Sites; D019281:Dimerization; D006131:Growth Inhibitors / Q000378:metabolism / Q000633:toxicity*; D007939:Leukemia L1210 / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D014404:Tubulin / Q000378:metabolism*; D050257:Tubulin Modulators; D014407:Tumor Cells, Cultured / Q000378:metabolism / Q000473:pathology; D014747:Vinblastine / Q000031:analogs & derivatives* / Q000633:toxicity; D014748:Vinca Alkaloids / Q000378:metabolism / Q000633:toxicity*; D000077235:Vinorelbine
D006131:Growth Inhibitors; D014404:Tubulin; D050257:Tubulin Modulators; D014748:Vinca Alkaloids; C111217:vinflunine; D014747:Vinblastine; D000077235:Vinorelbine