Commentary on “Apoptosis, p53, and Tumor Cell Sensitivity to Anticancer Agents”

Abstract

In 1999, a review on apoptosis, p53, and tumor cell sensitivity to anticancer agents was published in Cancer Research (1). TP53 is one of the most commonly mutated tumor suppressor genes in human cancer. This review accurately encapsulates the body of data collected at the time with regard to cells lacking p53 and their sensitivity to anticancer agents using short-term assays. Importantly, the authors of this review, Brown and Wouters, stress the importance of using long-term clonogenic assays to reveal the true sensitivity of cells to anticancer agents. This review in part led to a flurry of further investigation on p53 and its role in cancer and sensitivity to radiation, chemotherapy, and other anticancer agents.The major arguments laid out by the authors of this review are: (i) short-term assays can underestimate overall cell killing; (ii) p53 status did not seem to affect the sensitivity of cells of nonhematologic origin to genotoxic stress. The conclusions were contrary to the belief in the cancer field that tumor cells bearing p53 mutations were resistant to apoptosis and to cancer treatment (2-5). This review was written as a cautionary tale for investigators moving their studies from tissue culture-based work to in vivo mouse models. Many times, moving results from cell-based assays does not translate into effective use in vivo. Although the authors made very important points regarding the use of long-term clonogenic assays to assess the sensitivity of tumor cells to genotoxic agents, what was lacking at the time of publication were in vivo knockin mouse models with the p53 mutations that are commonly detected in human cancer patients. Over the last 17 years, several mouse models with p53 point mutations have been genetically engineered (6-9); two additional p53 family members, p63 and p73, were identified and found to contribute to p53 tumor suppression (10). Using these additional mouse models, novel insights and therapies to target the p53 pathway have been made.Two landmark articles with p53 hotspot mutations corresponding to p53R175H and p53R273H provided evidence of p53-mutant gain of function in cancer (7, 9). These mice displayed a distinct tumor spectrum to mice lacking p53, and also, tumors from these mice with p53 mutations metastasized (7, 9). Generation of these models also led to the ability to reactivate p53 in p53 nullizygous mice (11) and in those with mutant p53 (12) as a means for therapy. These mouse models show distinct mechanisms for p53 tumor suppression in different tumor types. Upon reactivation of p53 in p53 nullizygous mice, induction of apoptosis was critical for regression of lymphomas, while induction of cellular senescence is the key mechanism for regression of sarcomas (11); however, in mice with a p53 missense mutation, reactivation of p53 kept tumors from progressing but did not completely cause tumor regression (12). These results clearly indicate the differences between loss of p53 and the gain-offunction and dominant-negative effects of point mutant p53. Other mouse m...

Potensi Ekstrak Etanol 96% Daun Salam (Syzigium polyanthum Wight. (Walp.)) terhadap Ekspresi p53 pada Sel Kanker HeLa Cell Lines

“…Penelitian tersebut menginisiasi berbagai penelitian yang bertujuan untuk mengembangkan terapi kanker dan menemukan obat kanker. 6 Penelitian ini merupakan bagian dari sebuah penelitian yang melakukan eksplorasi daun Salam (Syzigium polyanthum Wight. (Walp.))…”