Potent inhibition of tumor survival in vivo by beta-lapachone plus taxol: combining drugs imposes different artificial checkpoints.
Ablation of tumor colonies was seen in a wide spectrum of human carcinoma cells in culture after treatment with the combination of beta-lapachone and taxol, two low molecular mass compounds. They synergistically induced death of cultured ovarian, breast, prostate, melanoma, lung, colon, and pancreatic cancer cells. This synergism is schedule dependent; namely, taxol must be added either simultaneously or after beta-lapachone. This combination therapy has unusually potent antitumor activity against human ovarian and prostate tumor prexenografted in mice. There is little host toxicity. Cells can commit to apoptosis at cell-cycle checkpoints, a mechanism that eliminates defective cells to ensure the integrity of the genome. We hypothesize that when cells are treated simultaneously with drugs activating more than one different cell-cycle checkpoint, the production of conflicting regulatory signaling molecules induces apoptosis in cancer cells. beta-Lapachone causes cell-cycle delays in late G(1) and S phase, and taxol arrests cells at G(2)/M. Cells treated with both drugs were delayed at multiple checkpoints before committing to apoptosis. Our findings suggest an avenue for developing anticancer therapy by exploiting apoptosis-prone "collisions" at cell-cycle checkpoints.
Li
C J
CJ
Division of Cell Growth and Regulation, Dana-Farber Cancer Institute, Department of Biological Chemistry, Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA. cjli@mbcrr.harvard.edu
Li
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YZ
Pinto
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Pardee
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D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects*; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D004357:Drug Synergism; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009285:Naphthoquinones / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000473:pathology*; D017239:Paclitaxel / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D009285:Naphthoquinones; C014638:beta-lapachone; D018844:Cyclin-Dependent Kinases; D017239:Paclitaxel