Nadhim Kamil Hante Alshiblawi

Aims We have recently described a novel guanidinium-based compound, VP79s, which induces cytotoxicity in various cancer cell lines. Here, we aim to investigate the activity of VP79s and associated mechanisms of action in multiple myeloma (MM) cells in vitro and ex vivo. Main methods The effects of VP79s on cell viability and induction of apoptosis was examined in a panel of drug-sensitive and drug-resistant MM cell lines, as well as ex vivo patient samples and normal donor lymphocytes and platelets. Cell signaling pathways associated with the biological effects of VP79s were analysed by immunoblotting and flow cytometry. Gene expression changes were assessed by quantitative real-time PCR analysis. Key findings VP79s was found to rapidly inhibit both constitutively active and IL-6-induced STAT3 signaling with concurrent downregulation of the IL-6 receptors, CD130 and CD126. VP79s induced a rapid and dose-dependent downregulation of anti-apoptotic Bcl-2 family member, myeloid cell leukaemia-1 (MCL-1). VP79s enhanced bortezomib induced cell death and was also found to overcome bone marrow stromal cell induced drug resistance. VP79s exhibited activity in ex vivo patient samples at concentrations which had no effect on peripheral blood mononuclear cells, lymphocytes and platelets isolated from healthy donors. Significance As VP79s resulted in rapid inhibition of the key IL-6/STAT3 signaling pathway and downregulation of MCL-1 expression with subsequent selective anti-myeloma activity, VP79s may be a potential therapeutic agent with a novel mechanism of action in MM cells.

The importance of doxorubicin (Dox), as a potent antitumor antibiotic, is limited by the developmentof life-threatening cardiomyopathy. It has been shown that free radicals are involved in acute doxorubicin-inducedtoxicity. The aim of this study was to determine the protective effect of vitamin E and telmisartan in acutedoxorubicin induced cardiotoxicity.Methods: Thirty two male Sprague - Dawly rats were involved in this study and were randomly separated into 4groups, eight rats in each group, one group received normal saline I.P as control and second group receiveddoxorubicin 20 mg/kg I.P, the other two groups also received doxorubicin 20 mg/kg I.P as single dose after sevencumulative doses (for seven days) of vitamin E (100 mg/kg) and telmisartan (1 mg/kg) respectively.Immunofluorescent staining for monocytes infiltration and analyses of plasma by (ELISAs) for MCP-1and troponin I.Western immunoblotting assay for ICAM-1, while left ventricular function was analyzed by microcatheter, alsoestimated the level of oxidative stress parameters (MDA and Catalase) and cardiac enzymes activities (CK-MB andLDH) before starting drugs treatment and after treatment period by 48 hours.Results: The immunofluorescent staining showed that administration of vitamin E and telmisartan are attenuatedof mononuclear cell infiltration; (p < 0.05 vs. Dox group), also reduced the level of chemokines MCP-1 and ICAM-1expression compared with Dox group only, and there is marked reduction of myocardial troponin-I levels withimproved LV function in vitamin E and telmisartan treated group. Doxorubicin treatment increased MDA, LDH,CK-MB levels significantly (P < 0.01), and were counteracted by administration of vitamin E and telmisartan, but didnot significantly affect serum catalase activity.Conclusions: Antioxidant effect (Vitamin E and telmisartan) have been shown to decreasedoxorubicininduced cardiotoxicity.