DRUG-RESISTANCE AGAINST GEMCITABINE AND TOPOTECAN MEDIATED BY CONSTITUTIVE HSP70 OVEREXPRESSION IN-VITRO - IMPLICATION OF QUERCETIN AS SENSITIZER IN CHEMOTHERAPY

Heat shock proteins have been reported to confer resistance to certain antineoplastic drugs. We investigated the impact of hsp70 overexpress ion on the efficacy of two new anti-cancer drugs, topotecan and gemcit abine. We used the fibrosarcoma WEHI-S cells stably transfected to ove rexpress the hsp70 cDNA from the constitutive SV40 promoter and approp riate control cells. After topotecan and gemcitabine treatment hsp70-o verexpressing cells showed a marked elevation in cell survival, sugges ting that hsp70 overexpression was sufficient to confer resistance to the drugs. ln addition, hsp70-overexpressing cells were capable of sta rting cell proliferation after treatment with drug dosages that were l ethal to control cells. Our results demonstrate that hsp70 overexpress ion represents a possible cause of drug resistance. In order to transf er these data to tumour cells constitutively expressing stress hsp70 d ue to the constitutive activity of the original hsp70 promoter we soug ht to supress the heat shock response pathway by the natural flavonoid quercetin, known to inactivate the heat shock transcription factor (H SF). Using a suitable cell line, we demonstrated the sensitising activ ity of quercetin. We found that antineoplastic drug concentrations exe rting cytotoxic activity were markedly lower when cells were pretreate d with quercetin. Concomitantly, hsp70 expression was strongly down-re gulated under quercetin treatment. Our data indicate that quercetin ma y be useful as a sensitiser in chemotherapeutically treated patients s uffering from hsp70-overexpressing tumours.