Abstract
BackgroundThe 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 [3H]VCR, and their ability to bind [14C]DXR and [3H]azidopine (AZD), a photoaffinity label of the multidrug transporter, P-glycoprotein (Pgp).ResultsTM effectively decreased the EC50 for DXR, EXR, VCR and CDDP, thus enhancing their cytotoxicity. The antibiotic also prolonged the intracellular retention time of [3H]VCR and increased the binding of both [14C]DXR and [3H]AZD to the cells.ConclusionIt 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.
Highlights
The pharmacologic modulatory effects of the antibiotic, tunicamycin (TM), on multidrug-resistant human UWOV2 ovarian cancer cells are reported
We examined the pharmacomodulatory effects of TM in the context of its interaction with the anticancer drugs doxorubicin (DXR), epirubicin (EXR), vincristine (VCR) and cisplatin, and the possible mechanistic relation of such combinations to the expression of drug resistance in human UWOV2 ovarian cancer cells
Cell culture of UWOV2 cells The UWOV2 ovarian carcinoma cell line, derived from a cystadenocarcinoma in a patient who had not responded to combination chemotherapy with actinomycin D, vincristine, cisplatin and doxorubicin [75], was maintained in RPMI-1640 medium supplemented with 5% heat-inactivated foetal calf serum (HIFCS), penicillin G (100 U/ml) and streptomycin sulphate (100 μg/ml) or gentamicin sulphate (50 μg/ml) at 37°C in 5% CO2:air and 85% relative humidity
Summary
The pharmacologic modulatory effects of the antibiotic, tunicamycin (TM), on multidrug-resistant human UWOV2 ovarian cancer cells are reported. The role of post-translational modification of proteins, such as N-glycosylation, in normal and transformed processes is well documented [1,2,3,4,5,6,7,8,9] This knowledge has prompted explicit pharmacological interest in compounds that can interfere with glycoprotein processing at the cellular level [1,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19]. A notable corollary in this regard is the finding that bortezomib [19,21], a potent and selective inhibitor of the ubiquitin-proteasome system (UPS, which likewise serves to identify and remove malformed proteins [19,45,52], is proapoptotic – an effect triggered by TM and thapsigargin (classic ER stress inducers) via a c-Jun-terminal kinase (JNK)dependent mechanism [21]
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