Title:Cyclophilin A as a Target of Cisplatin Chemosensitizers
Volume: 14
Issue: 1
Author(s): Gerhard Hamilton
Affiliation:
Keywords:
CD147, chemotherapy, cisplatin, cyclophilin, cyclosporin, drug resistance, ovarian cancer, reactive oxygen species,
sanglifehrin.
Abstract: 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.
