Besides, caspase 4 mRNA levels were also up-regulated

by the same combination. In the literature, there is a body of evidence showing that exposure to ATRA results in the upregulation of cell surface Endocrinology antagonist expression of TNFRs in some type of cancer cells [27]. Thus, exposure of cancer cells with ATRA and zoledronic acid combination results in strong apoptotic stimuli through TNFRs. The Bcl-2 family proteins are central regulators of apoptosis because they integrate diverse survival and death signals that are generated outside and inside the cell [28, 29]. The combination treatment in our study resulted downregulation of some important Bcl-2 antiapoptotic members (Bcl-2 L1, Bcl-2 L12, Bcl-2 L13) whereas an MAPK inhibitor induction in proapoptotic family member

(the Bcl-2/adenovirus E1B-19K interacting protein BNIP3) was observed. Besides, there was a downregulation of mRNA levels of BAG3 with ATRA and zoledronic acid combination. BAG-3 (Bis) has also been reported to associate with the anti-apoptotic protein Bcl-2 [30]. Functional analysis revealed that BAG-3 itself exerts only weak anti-apoptotic activity, but acts synergistically with Bcl-2 this website in preventing Bax-induced and FasL/Fas-mediated apoptosis mRNA levels of MCL-1 and LTBR genes were also reduced by the combination treatment. The MCL-1 gene was discovered incidentally as an induction gene in myeloblastic leukemia cell differentiation about a decade ago and proved to be a member of the emerging Bcl-2 gene family [31]. LTBR is also a very good example of two-way functioning molecules. LTBR is a member of TNFRSF that regulate cell survival or death through activation of nuclear factor kappa B (NF-kappaB). In

some studies, it was clearly shown that by binding LTBR with some specific or oligo-sense antibodies resulted in decreased tumor growth and increased Edoxaban apoptosis in tumor cells [32–34]. Our oligo array results were also verified with RT- PCR assay, and the results highly correlated with each other. Of these genes, TNFRSF1A and TRADD were found to be upregulated since they work as the trigger molecules of the apoptotic cascade in cancer cells whereas antiapoptotic genes MCL-1 and LTBR were found to be downregulated. Conclusions Retinoids are widely investigated as the enhancers of cytotoxic agents in cancer treatment. Since they do not have any significant toxic side effect, they represent good candidates for combination treatment. Zoledronic acid, far beyond its effect on bone turn over, has presented some novel antitumoral activity even in the adjuvant treatment of cancer. So, in conclusion, these findings provide basic molecular information for further investigation on the mechanisms by which ATRA and zoledronic acid exert their pleiotropic effects in ovarian cancer cells.