Enhancement of the antiproliferative effect of <i>cis</i>‐diamminedichloroplatinum(II) and nitrogen mustard by inhibitors of protein kinase C

International Journal of Cancer - Tập 42 Số 3 - Trang 382-388 - 1988
Johann Hofmann1, Wolfgang Doppler2, Axel Jakob2, Karl Maly2, Lydia Posch2, Florian Überall2, H. Grunicke2
1Institut für Medizinische Chemie und Biochemie, Universität Innsbruck, Austria
2Institut für Medizinische Chemie und Biochemie, Universität Innsbruck, Innsbruck, Austria

Tóm tắt

AbstractQuercetin (3, 3′, 4′, 5, 7‐pentahydroxyflavone) has been shown to inhibit a variety of enzymes including the calcium‐ and phospholipid‐dependent protein kinase (protein kinase C) in vivo and in vitro. We show that this compound synergistically enhances the antiproliferative activity of cis‐diamminedichlo‐roplatinum(II) (cis‐DDP) and nitrogen mustard. Quercetin does not affect the repair of DNA interstrand cross‐links introduced by cis‐DDP. Long‐term exposure to 12‐O‐tetradeca‐noylphorbol‐13‐acetate (TPA), which reduces total protein kinase C activity, also amplifies the growth‐inhibitory effect of cis‐DDP and acts synergistically with quercetin. A synergism is also observed if tamoxifen or staurosporine are combined with cis‐DDP. For both drugs the dose‐effect curves for the inhibition of protein kinase C closely resemble the dose‐effect curves for the antiproliferative activities. Although alternative mechanisms cannot be definitively excluded, the effects of quercetin, TPA, tamoxifen and staurosporine may result from the inhibition of protein kinase C.

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