Platinum-based chemotherapeutics are the mainstay of treatment of a range of
tumors achieving high response rates but limited in the course of disease by appearance of drug resistance.
Tumor cells respond with reduced uptake and increased intracellular inactivation of the drugs, as well as increased DNA repair and general resistance to chemotherapyinduced cell death.
Cisplatin is known to induce expression of
cyclophilins, a group of
proteins that have
peptidyl-prolyl cis-trans isomerase (
PPIase) and
molecular chaperone activities, as stress response.
Cyclophilin A (CypA) and other members of this family are inhibited by
cyclosporin A (CsA) which sensitized diverse
drug-resistant tumor cell lines in vitro to
cisplatin. This effect of CsA was attributed to metabolic changes, inhibition of DNA repair, enhancement of apoptosis, altered intracellular signal transduction or increased production of
reactive oxygen species (ROS), although no definitive explanation was provided so far. Several clinical trials employing
cisplatin/
carboplatin in combination with CsA yielded unsatisfactory results. Since viral replication was found to be dependent on
cyclophilins of the host cells, effective new inhibitors, different from CsA or with low or absent immunosuppressive activity, are in development or clinical trials. Sanglifehrins are more potent than CsA and proved to increase toxicity of
cisplatin against
hepatocellular cancer cells in vitro. These novel
cyclophilin inhibitors may offer new opportunities to achieve reversal of resistance to platinumbased drugs in refractory patients. Responsive
cancer patients may be enriched in clinical trials by an identification of the downstream targets of Cyps responsible for chemoresistance.