A Phase IIb Trial Assessing the Addition of Disulfiram to Chemotherapy for the Treatment of Metastatic Non-Small Cell Lung Cancer

Abstract

Background. Disulfiram, an alcohol aversion agent, has been in use for .50 years. Numerous authors have reported an anticancer effect of this drug in vitro and in mouse models. More recently, several reports have claimed that disulfiram also possesses anti-stem cell activity. We set out to obtain initial data regarding the safety of combining this drug with chemotherapy and the possible effectiveness of disulfiram in a combination regimen in non-small cell lung cancer (NSCLC). Methods. This phase II, multicenter, randomized, doubleblinded study assessed the safety and efficacy of adding of disulfiram to cisplatin and vinorelbine for six cycles. Newly diagnosed NSCLC patients were recruited. Patients with either stage IV or what was considered at the time "wet IIIb" (since 2009, these patients have been considered stage IV) were recruited. The patients were treated with only chemotherapy, and none were treated with either surgery or chemoradiation. Disulfiram was administered at a dose of 40 mg three times daily. Results. Forty patients were treated for more than two cycles, half with and half without disulfiram, which was well tolerated. An increase in survival was noted for the experimental group (10 vs. 7.1 months). Interestingly, there were only two longterm survivors, both in the disulfiram group. Conclusion. The addition of disulfiram to a combination regimen of cisplatin and vinorelbine was well tolerated and appeared to prolong survival in patients with newly diagnosed non-small cell lung cancer. The results from this small study seem encouraging enough forassessment inlarger trials.Disulfiramis an inexpensive and safe drug; if its addition to chemotherapy could be shown to

Anti-hepatocellular carcinoma properties of the anti-alcoholism drug disulfiram discovered to enzymatically inhibit the AMPK-related kinase SNARK in vitro

“…Another attractive feature of DSF is the tolerability and safety demonstrated over years of clinical experience with a large number of patients, and also in the NSCLC patients [34]. Plasma concentrations of DSF in several reports [37, 38], reaching even above 100 μM, routinely exceeded the IC 50 of the in vitro kinase assay described here, so SNARK inhibitory concentrations are expected to be achieved safely in patients.…”

Redox-Active Mn Porphyrin-based Potent SOD Mimic, MnTnBuOE-2-PyP5+, Enhances Carbenoxolone-Mediated TRAIL-Induced Apoptosis in Glioblastoma Multiforme

“…Thus, such MnPs are prospective for clinical development as enhancers of ascorbate/H 2 O 2 driven cancer cell killing. CBX is clinically approved for the treatment of esophageal ulceration [41], and different natural compounds as sulfur donors, such as garlic components [42], disulfiram [43], or even the simpliest thiol, H 2 S, bear therapeutic potential [44]. MnBuOE, which we used herein, has excellent safety profile, and shows excellent radioprotection in preclinical studies [14, 15, 24, 45].…”

Inhibition of Proteasomal Deubiquitinase by Silver Complex Induces Apoptosis in Non-Small Cell Lung Cancer Cells

“…A growing body of evidence suggests that DSF possesses potential anti-tumor activities both in vitro and in vivo [17][18][19]. The addition of DSF to a combination regimen of cisplatin and vinorelbine appeared to prolong survival in patients with newly diagnosed NSCLC in clinical trials [20]. In this work, we have demonstrated that Ag ions alone or the combination of Ag ions and DSF induces the accumulation of ubiquitinated proteins mainly through inhibition of proteasomal DUBs.…”