Combination of tunicamycin with anticancer drugs synergistically enhances their toxicity in multidrug-resistant human ovarian cystadenocarcinoma cells

BACKGROUND: The pharmacologic modulatory effects of the antibiotic, tunicamycin (TM), on multidrug-resistant human UWOV2 ovarian cancer cells are reported. The UWOV2 cell line was derived from a cystadenocarcinoma in a patient refractory to combination chemotherapy with actinomycin D, vincristine (VCR), cis-diaminedichloroplatinum (II) (CDDP) and doxorubicin (DXR). In an attempt to explain drug resistance in this cell line, we examined the effects of TM on their sensitivity to various anticancer drugs, the uptake, efflux and retention of [(3)H]VCR, and their ability to bind [(14)C]DXR and [(3)H]azidopine (AZD), a photoaffinity label of the multidrug transporter, P-glycoprotein (Pgp). RESULTS: TM effectively decreased the EC(50 )for DXR, EXR, VCR and CDDP, thus enhancing their cytotoxicity. The antibiotic also prolonged the intracellular retention time of [(3)H]VCR and increased the binding of both [(14)C]DXR and [(3)H]AZD to the cells. CONCLUSION: It is concluded that the pharmacomodulatory effects of TM in these cells are mediated by global inhibition of protein and glycoprotein synthesis and synergistic interaction with antineoplastic drugs. The ability of TM to enhance the sensitivity of drug resistant tumour cells may have impact on the design and optimization of novel resistance modifiers to improve the efficacy of combination treatment of intractable neoplasms.