Role of apoptotic response in cellular resistance to cytotoxic agents

Franco Zunino, Paola Perego, Silvana Pilotti, Graziella Pratesi, Rosanna Supino, Federico Arcamone

Research output: Contribution to journalArticle

Abstract

The development of drug resistance is a major obstacle to effectiveness of chemotherapeutic treatment of human tumors with cytotoxic agents. Drug resistance is described as a multifactorial phenomenon, involving the expression of defense factors and/or detoxification mechanisms, alterations in drug-target interactions, and cellular response to specific cytotoxic lesions (in particular, DNA damage). Although the proposed mechanisms may contribute to the development of a variable degree of cellular resistance, it is possible that the cell response (i.e., DNA repair or apoptosis) following DNA damage plays a critical role in determining cellular chemosensitivity. The preclinical observations that tumor response to effective drug treatments is associated with induction of apoptosis support the possibility that a decreased susceptibility to apoptosis (apoptosis resistance) is relevant to clinical resistance. A number of molecular alterations associated with transformation and/or tumor progression may also be implicated in regulation of cell death pathways and in the development of drug resistance. There is evidence that the wild-type p53 is involved in cellular response to DNA damage, including cell cycle regulation, DNA repair, and activation of the pathway leading to apoptosis. Loss of wild-type p53 function could cause resistance to DNA-damaging agents, as a consequence of abrogation of p53- dependent apoptosis. The identification of new agents able to trigger p53- independent apoptosis and the search for biochemical modulators downstream of p53 may be of clinical relevance because many tumors are deficient in p53 function due to mutation or deletion. An overview of the resistance mechanisms is presented, with particular reference to the role of p53 mutations in clinical resistance and of apoptosis-related genes in cellular chemosensitivity.

Original languageEnglish
Pages (from-to)177-185
Number of pages9
JournalPharmacology and Therapeutics
Volume76
Issue number1-3
DOIs
Publication statusPublished - 1997

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Keywords

  • Apoptosis
  • Bcl-2
  • DNA damage
  • Drug resistance
  • p53

ASJC Scopus subject areas

  • Pharmacology

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