Inhibition of p53 Response in Tumor Stroma Improves Efficacy of Anticancer Treatment by Increasing Antiangiogenic Effects of Chemotherapy and Radiotherapy in Mice

Abstract

Inactivation of p53 function, which frequently occurs in tumors, can significantly modulate tumor cell sensitivity to radiation and chemotherapeutic drugs. However, in addition to acting on malignant cells, anticancer agents act on the cells of tumor stroma, causing activation of a p53 response. The effect of this response on treatment outcome has been the subject of the present study. Tumors with p53-deficient stroma were generated using mouse tumorigenic packaging cells that produce a p53 inhibitory retrovirus, encoding a dominantnegative p53 mutant. Tumors maintaining wild-type p53 in their stroma were formed by cells of similar origin but deficient in retroviral production due to the deletion of the packaging signal in the retroviral vector. Comparison of these tumor models, differing only in p53 status of their stromas, showed that tumors with p53-deficient stroma were significantly more sensitive to experimental chemotherapy and radiotherapy. A similar effect was achieved when anticancer treatment was combined with pharmacologic suppression of p53 by the cyclic form of pifithrin A, a small-molecule inhibitor of p53. Potentiation of the anticancer effect of chemotherapy and radiotherapy by p53 suppression in the tumor stroma is likely to be due to the increased sensitivity of p53-deficient endothelium to genotoxic stress as shown both in cell culture and in experimental tumors. Thus, reversible pharmacologic suppression of p53 may be a viable approach to improving anticancer treatment via an enhanced antiangiogenic effect of chemotherapy and radiotherapy.

p53 promotes cellular survival in a context-dependent manner by directly inducing the expression of haeme-oxygenase-1

“…It was noted long back that low levels of p53 can protect cells from serum withdrawal-mediated death (Lassus et al, 1996). Similarly, p53 was shown to function as a survival factor in the gastrointestinal tract under conditions of severe irradiation, which was attributed to increased sensitivity of vascular endothelial cells (Komarova et al, 2004;Burdelya et al, 2006). Furthermore, other reports have identified conditions in which absence of p53 led to elevated apoptosis, but a direct causal role for p53 in providing survival signals has not been described (Lassus et al, 1996;Lackinger and Kaina, 2000;Hermisson et al, 2006;Batista et al, 2007;Roepke et al, 2007;Roos et al, 2007).…”

Short-term inhibition of p53 combined with keratinocyte growth factor improves thymic epithelial cell recovery and enhances T-cell reconstitution after murine bone marrow transplantation

“…31 Collective preclinical data argue that temporary and reversible inhibition of p53 with pharmacologic inhibitors such as PFT-␤ does not predispose recipients to develop tumors. [31][32][33][67][68][69][70] In fact, accumulating evidence indicates that transient inhibition of p53 during radiation conditioning regimens may actually promote eradication of solid tumors through destruction of stromal support and/or the tumor itself and increase efficacy of chemoradiotherapy conditioning. 33 Ongoing efforts are aimed at identifying pharmacologic modulators of p53 to inhibit singular functions of p53.…”

“…[31][32][33][67][68][69][70] In fact, accumulating evidence indicates that transient inhibition of p53 during radiation conditioning regimens may actually promote eradication of solid tumors through destruction of stromal support and/or the tumor itself and increase efficacy of chemoradiotherapy conditioning. 33 Ongoing efforts are aimed at identifying pharmacologic modulators of p53 to inhibit singular functions of p53. One candidate molecule (termed PFT-) reversibly inhibits p53 binding to mitochondria, but, unlike PFT-␤, it does not affect p53 transactivation functions.…”

“…15 PFT-␤ is a cyclic derivative of the small molecule inhibitor, pifithrin-alpha (PFT-␣), that is significantly less toxic and possesses longer pharmacodynamic effects than does PFT-␣. 33 PFT-␤ was administered intraperitoneally (25 mg/kg) in phosphate-buffered saline (PBS) 30 to 45 minutes before radiation. The dose/timing of PFT-␤ administration provides optimal inhibition of p53 function with minimal toxicity 32 (data not shown).…”

Pifithrin-α protects against DNA damage-induced apoptosis downstream of mitochondria independent of p53

“…To overcome such deleterious complications, the small chemical p53 inhibitor, PFT-a, was identified, which protected mice from otherwise lethal doses of radiation. 4 As p53 proficiency is not always associated with a better prognosis and might in some instances even protect tumor cells from DNA damage-induced apoptosis, [24][25][26] the concept of p53 inactivation by PFT-a might be worth considering even in such cases. 27 In any case, this concept is only valid provided PFT-a prevents apoptosis solely through inhibition of p53, as an interference with additional apoptosis signaling components unrelated to p53, but common to normal and tumor cells, might adversely affect any therapeutic intervention.…”