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

TY - JOUR

T1 - An evaluation of small-molecule p53 activators as chemoprotectants ameliorating adverse effects of anticancer drugs in normal cells

AU - van Leeuwen, Ingeborg M. M.

AU - Rao, Bhavya

AU - Sachweh, Marijke C. C.

AU - Lain, Sonia

PY - 2012/5/1

Y1 - 2012/5/1

N2 - 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.

AB - 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.

U2 - 10.4161/cc.20254

DO - 10.4161/cc.20254

M3 - Article

C2 - 22517433

SN - 1538-4101

VL - 11

SP - 1851

EP - 1861

JO - Cell Cycle

JF - Cell Cycle

IS - 9

ER -