novobiocin and Carcinoma--Non-Small-Cell-Lung

Novobiocin, a commercially available oral antibiotic, inhibits DNA topoisomerase II in a manner shown in cell culture to enhance the cytotoxicity of alkylating agents and cisplatin. Thirty-six patients were entered on a Phase II trial using high-dose cisplatin (100 mg/m2 on days 1 and 8 for four cycles) after steady-state dosing with novobiocin (1000 mg or four 250-mg capsules every 12 hours for six doses, four of which were administered before each dose of cisplatin). One patient remains on study and cannot be evaluated for response. No complete responses were seen. Three patients (8%) had partial responses and an additional patient had an unconfirmed partial response. The median survival time of all patients was just less than 7 months. These results are comparable with those of other concurrent Southwest Oncology Group (SWOG) Phase II and III trials of high-dose cisplatin in non-small cell lung cancer (NSCLC). Novobiocin plasma levels were obtained for three patients and were approximately 50% of the optimal concentration as reported in cell culture for potentiation of cytotoxicity. It was concluded that an optimum test of novobiocin as a modulator of cytotoxicity may require the availability of an intravenous preparation.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Capsules; Carcinoma, Non-Small-Cell Lung; Cisplatin; Drug Evaluation; Female; Humans; Infusions, Intravenous; Kidney; Lung Neoplasms; Male; Middle Aged; Novobiocin; Remission Induction; Southwestern United States

Heat shock protein 70 (Hsp70) and heat shock protein 90 (Hsp90) chaperones are indispensable to lung cancer cells for their survival and proliferation. In this study we evaluated and compared anticancer potential of methylene blue (MB) as an Hsp70 inhibitor, novobiocin (NB) a well-known Hsp90 inhibitor and their combination.. In vitro evaluation was done by cell viability assays, fluorescent staining, and flow cytometry analysis using A549 non-small cell lung cancer cells. In vivo anticancer activity was investigated by evaluating oxidative stress, tumor biomarkers, weight, lung microarchitecture, and Hsp70 and Hsp90 inhibitions via immunoblotting in benzo[a]pyrene induced lung carcinogenesis mice model.. Using A549 NSCLC cells, we found MB demonstrated lower cell viability versus NB. Together, MB + NB resulted in further decrease in cell viability. SRB assay revealed significantly superior and similar potency for MB versus NB and MB + NB (1:1) versus MB, respectively. Fluorescent staining and flow cytometry analysis displayed early apoptosis by MB (11.4%); early and late apoptosis by MB + NB (13.8%). In vivo, MB significantly inhibited Hsp70. Furthermore, MB significantly alleviated tumor biomarkers (ADA and LDH) and improved lung histopathological features more than NB. Additionally, MB significantly improved SOD, not more than MB + NB or NB and improved LPO.. MB demonstrated potent anticancer activity in vitro and in vivo via inhibition of Hsp70 in benzo[a]pyrene induced lung carcinogenesis in mice.

Topics: A549 Cells; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Benzo(a)pyrene; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Cell Proliferation; Cell Survival; Flow Cytometry; HSP70 Heat-Shock Proteins; HSP90 Heat-Shock Proteins; Humans; Lung Neoplasms; Male; Methylene Blue; Mice; Novobiocin; Oxidative Stress