An evaluation of small-molecule p53 activators as chemoprotectants ameliorating adverse effects of anticancer drugs in normal cells

Ingeborg M. M. van Leeuwen, Bhavya Rao, Marijke C. C. Sachweh, Sonia Lain

    Research output: Contribution to journalArticle

    34 Citations (Scopus)

    Abstract

    Pharmacological activation of wild-type p53 has been found to protect normal cells in culture from cytotoxicity and nuclear aberrations caused by conventional cancer therapeutics. Hence, small-molecule p53 activators could have clinical benefits as chemoprotectants for cancer patients bearing p53-mutant tumors. We have evaluated 16 p53-based cyclotherapy regimes combining p53 activators tenovin-6, leptomycin B, nutlin-3 and low dose actinomycin D, with clinically utilized chemotherapeutic agents (S-and M-phase poisons) vinblastine, vinorelbine, cytosine arabinoside and gemcitabine. All the p53 activators induce reversible cell cycle arrest in primary human fibroblasts and protect them from both S-and M-phase poisons. Furthermore, studies with p53-mutant cancer cell lines show that nutlin-3 and low-dose actinomycin D do not affect the sensitivity of these cells to any of the chemotherapeutics tested. Thus, these two small molecules could be suitable choices for cyclotherapy regimes involving S- or M-phase poisons. In contrast, pre-incubation of p53-mutant cells with tenovin-6 or leptomycin B reduces the efficacy of vinca alkaloids, suggesting that these p53 activators could be effective as chemoprotectants if combined with S-but not M-phase poisons. Discrepancies were observed between the levels of protection detected immediately after treatment and following recovery in fresh medium. This highlights the need to assess both short-and long-term effects when evaluating compounds as potential chemoprotectants for cancer therapy.

    Original languageEnglish
    Pages (from-to)1851-1861
    Number of pages11
    JournalCell Cycle
    Volume11
    Issue number9
    DOIs
    Publication statusPublished - 1 May 2012

    Cite this

    van Leeuwen, Ingeborg M. M. ; Rao, Bhavya ; Sachweh, Marijke C. C. ; Lain, Sonia. / An evaluation of small-molecule p53 activators as chemoprotectants ameliorating adverse effects of anticancer drugs in normal cells. In: Cell Cycle. 2012 ; Vol. 11, No. 9. pp. 1851-1861.
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    An evaluation of small-molecule p53 activators as chemoprotectants ameliorating adverse effects of anticancer drugs in normal cells. / van Leeuwen, Ingeborg M. M.; Rao, Bhavya; Sachweh, Marijke C. C.; Lain, Sonia.

    In: Cell Cycle, Vol. 11, No. 9, 01.05.2012, p. 1851-1861.

    Research output: Contribution to journalArticle

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    AU - Rao, Bhavya

    AU - Sachweh, Marijke C. C.

    AU - Lain, Sonia

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