Selective targeting of tumorigenic cancer cell lines by microtubule inhibitors.
For anticancer drug therapy, it is critical to kill those cells with highest tumorigenic potential, even when they comprise a relatively small fraction of the overall tumor cell population. We have used the established NCI/DTP 60 cell line growth inhibition assay as a platform for exploring the relationship between chemical structure and growth inhibition in both tumorigenic and non-tumorigenic cancer cell lines. Using experimental measurements of "take rate" in ectopic implants as a proxy for tumorigenic potential, we identified eight chemical agents that appear to strongly and selectively inhibit the growth of the most tumorigenic cell lines. Biochemical assay data and structure-activity relationships indicate that these compounds act by inhibiting tubulin polymerization. Yet, their activity against tumorigenic cell lines is more selective than that of the other microtubule inhibitors in clinical use. Biochemical differences in the tubulin subunits that make up microtubules, or differences in the function of microtubules in mitotic spindle assembly or cell division may be associated with the selectivity of these compounds.
Abdullah
Newaj M
NM
Department of Pharmaceutical Sciences, University of Michigan College of Pharmacy, Ann Arbor, Michigan, United States of America.
Rosania
Gus R
GR
Shedden
Kerby
K
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor / Q000187:drug effects* / Q000378:metabolism; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D020869:Gene Expression Profiling; D006801:Humans; D008870:Microtubules / Q000378:metabolism*; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism; D050257:Tubulin Modulators / Q000737:chemistry / Q000494:pharmacology*
D000970:Antineoplastic Agents; D014404:Tubulin; D050257:Tubulin Modulators