Temporary Inhibition of p53 for Reduced Side Effects in Anticancer Therapy

10 September, 1999

Temporary Inhibition of p53 for Reduced Side Effects in Anticancer Therapy

One of the major problems in cancer chemotherapy and radiation therapy is the severe side effects that limit their efficacy. What are possible determinants of these side effects? The control of these side effects would greatly enhance the quality of life of cancer patients under these treatments. The anticancer therapy damages several normal tissues such as lymphoid and hematopoietic organs, intestinal epithelia, and the testis. Gamma irradiation induces p53-dependent apoptosis in these sensitive tissues where the p53 gene is highly expressed , and p53-deficient mice survive higher doses of gamma irradiation because of bone marrow resistance than do wild-type animals (Westfal CH et al,1998: uid=9865712). It was indicated previously that in a physiological range, low levels of the p53 protein protect fibroblasts from induction of apoptosis, and that as a function of its dose, the wild-type p53 can either protect from cell death or promote apoptosis (Lassus P et al, 1996: uid=8887548). p53 therefore appears to define both the efficacy and limitations of anti-cancer treatment. These observations suggest a notion that temporary suppression of p53 might be a workable therapeutic strategy to prevent damage of normal tissues during anticancer treatment and to result in reduced side effects.
To explore the feasibility of this approach, Komarov PG et al (1999: uid=10481009) isolated a chemical inhibitor of p53 and characterized its effects in vitro and in vivo. The bacterial lacZ reporter gene was put under the control of a p53-responsive promoter in the mouse ConA cell line for compound screening, and selected compounds were further tested in a conventional model cell (mouse cell line C8) of p53-dependent apoptosis. A diverse collection of ca 100,000 synthetic compounds were tested for p53 inhibition in the screening system where p53 was highly induced by a powerful inducer, doxorubicinin. Those compounds were selected that attenuated beta-Gal induction in doxorubicin-treated cells with no effect on cell growth or survival rate. Pifithrin-alpha (PFTalpha) with the chemical structure [2-(2-imino-4,5,6,7-tetrahydrobenzothiazol-3-yl)-1-p-tolylethanone] was chosen for a detailed characterization. This water-soluble and stable compound (MW 367) blocked activation of p53-responsive lacZ in ConA cells that was induced not only by doxorubicin but also by ultraviolet light and gamma radiation in a dose-dependent manner. At a 10 uM concentration, PFTalpha inhibited apoptotic death of C8 cells induced by doxorubicin, etoposide, Taxol, cytosine arabinoside, UV light, and gamma radiation. Similarly, PFTalpha inhibited p53-dependent growth arrest of human diploid fibroblasts in response to DNA damage but had no effect on p53-deficient fibroblasts. To analyze the in vivo effects of PFTalpha, two different strains of mice (C57BL and Balb/c) were treated with lethal and sublethal doses of whole-body gamma radiation tested for PFTalpha effect. PFTalpha treatment completely rescued mice of both strains from 60% killing doses of gamma irradiation (8 Gy for C57BL and 6 Gy for Balb/c). However, PFTalpha did not protect p53-null mice from lethal irradiation.

p53 functions as a key component of a cellular emergency response mechanism. A variety of stress signals induce p53 for growth arrest or apoptosis at least in part through the activation of its down-stream genes such as p21CIP1/WAF1, GADD45 and BAX, thereby eliminating damaged and potentially dangerous cells from the organism. On the other hand, the p53 gene is lost or mutated in most human tumors, and deficiency of functional p53 is accompanied by high rates of genomic instability and rapid tumor progression. Much effort has been made to facilitate anticancer treatment by restoring p53 function in cancer cells. The finding summarized above indicates an additional role of p53 in cancer treatment, namely, that temporary inhibition of p53 might be useful for reducing the side effects of cancer therapy and other type of stress associated with p53 induction.

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