Inhibition of nuclear factor kappa B transcription activity drives a synergistic effect of pyrrolidine dithiocarbamate and cisplatin for treatment of renal cell carcinoma

Abstract

One of the impeding factors in the effective treatment of metastatic renal cell carcinoma (RCC) is their intrinsic and acquired resistance to chemotherapeutics. Many studies have shown that drug resistance, at least in part, is mediated by the upregulation of anti-apoptotic (Bcl-2) and multidrug resistance molecules (MDR-1 and MRP-1) by the transcription factor nuclear factor kappa B (NF-kappaB). Combining NF-kappaB inhibitors with conventional chemotherapeutics could overcome resistance of cancer cells. In this study, we examined the synergistic effect of pyrrolidine dithiocarbamate (PDTC), a NF-kappaB inhibitor, and cisplatin, on two human metastatic RCC cell lines ACHN and SN12K1. Individual non-toxic concentrations of PDTC and cisplatin, when combined, synergistically induced a significant increase in apoptosis of the two RCC cell lines. In ACHN cells, the groups with nuclear translocation of NF-kappaB showed resistance to apoptosis, but in SN12K1 cells, the groups with NF-kappaB translocation were susceptible to apoptosis. The combination treatment significantly decreased the transcription activity of all NF-kappaB subunits in both cell lines. Anti-apoptotic proteins Bcl-2 and Bcl-(XL) were significantly decreased in the combination therapy group of both cell lines, but MDR-1 was decreased only in the ACHN cells. No changes in MRP-1 were observed in any of the treatment groups. The results demonstrate the potential of PDTC to be an adjunct therapeutic agent. The major mechanism of the synergistic effect appears to be mediated by the inhibition of transcription activity of NF-kappaB rather than its expression, and the resultant decrease in the anti-apoptotic proteins Bcl-2 and Bcl-(XL).

Pyrrolidine dithiocarbamate inhibits enterovirus 71 replication by down-regulating ubiquitin–proteasome system

“…In consistent with most reported studies, (Chen et al, 2006Liang et al, 2004;Lu et al, 2013;Shi et al, 2012;Shih et al, 2008), this study demonstrated that EV71 induced apoptosis as early as 8 h of p.i. In contrast, study by Morais et al (2010) and Zheng et al (2014) showed that, when combined with cisplatin, PDTC significantly induced apoptosis in human cancer cells. On the other hand, study by Thompson et al (2010) has shown that PDTC blocks apoptosis in normal mouse spleen cells.…”

“…Pyrrolidine dithiocarbamate (PDTC) is a synthetic compound, which is largely used as antioxidant or nuclear factor kappa B (NF-B) inhibitor (Morais et al, 2010;Wiesener et al, 2011;Yucel et al, 2013). Previous studies have shown that PDTC could inhibit the replication of coxsackievirus B3 (CVB3), rhinovirus, influenza virus, and herpes simplex virus (Krenn et al, 2005;Qiu et al, 2013;Si et al, 2005;Uchide and Ohyama, 2003;Uchide et al, 2002;Wiesener et al, 2011), while the precise mechanism involved in the antiviral activity of PDTC has not been elucidated.…”

Paeoniflorin modulates multidrug resistance of a human gastric cancer cell line via the inhibition of NF-κB activation

“…Therefore, NF-κB is proposed as a specific molecule related to drug resistance and is a potential therapeutic target for the treatment strategy of gastric carcinoma. For instance, PDTC and MG132 (NF-κB inhibitors), are capable of inhibiting cell proliferation and reversing MDR in human gastric, and other types of cancer cells (29)(30)(31). It has also been reported that cyclosporin A is capable of enhancing taxotere-induced apoptosis in human gastric carcinoma cells, mainly via the inhibition of NF-κB activation (32).…”

Synergistic Effect of Pyrrolidine Dithiocarbamate and Cisplatin in Human Cervical Carcinoma

“…8,9 Importantly, in some cell lines, PDTC has been shown to inhibit NF-kB activation. 10 To date, no report has been published about the concentration-dependent actions of this agent in human cervical carcinoma SiHa cells. There is also no information available as to whether PDTC can increase the sensitivity of SiHa cells in a concentration-dependent manner to differing doses of cisplatin by affecting the activation of NF-kB.…”