How to kill cancer cells: membranes and cell signaling as targets in cancer chemotherapy.
Most approaches to cancer chemotherapy have centered around the idea that cytotoxic drugs can be used to eradicate proliferating neoplastic cells. Cytotoxicity is generally thought to evolve from the presence of drug-induced damage to the genetic material, and DNA has served admirably as a primary focus for drug development. Other cellular targets should also be vulnerable, however, and over the past decade the plasma membrane in particular has received considerable attention as a therapeutic locus. In the early stages of this work there were only vague notions as to how membrane disruption could lead to cell death, but recent thinking has coalesced around the idea that cell-surface signal transduction and growth control pathways represent an ideal target for the rational development of new cancer therapies. In this review, we discuss three aspects of signal transduction-phosphoinositide turnover, phosphorylation by protein kinase C, and phosphorylation by protein tyrosine kinases--and summarize the existing evidence that these vital processes can be specifically disrupted, and that such pharmacology offers rich prospects for future therapeutic design.