Anti-FASL monoclonal antibody, clone MFL4

Objective: Epidemiologic studies showed that nutrition plays a role in incidence of cancer. However, little is known if nutrition also modulates the effect of chemotherapeutics. For this purpose, the present study investigates the cytotoxic effect of olive leaf extract and its combination with epirubicin. Method: Cell viability was measured via ATP assay on MDA-MB-231 and MCF-7 cell lines. Apoptosis was detected by poly(ADP-ribose) polymerase (PARP) cleavage, and the expression of apoptosis-related genes. A single extract was used throughout the study. Results: Both olive leaf extract and epirubicin resulted in cytotoxic effect in a dose-dependent manner in both cell lines. The extract further increased the cytotoxic effect of epirubicin in MDA-MB-231 cell line. However, in contrast, it abolished the cytotoxic effect of epirubicin in MCF-7 cell line. As a confirmative result, the increased expressions of FASLG and HRK following epirubicin treatment were down-regulated when epirubicin was used in combination with the extract in MCF-7 cells. Conclusion: Olive leaf extract modulates the cytotoxic effect of epirubicin when it is in combination depending on the type of cell line. This warrants further in vivo experiments for better understanding of this intriguing result.

Therapeutic efficacy of first-generation hypomethylating agents (HMAs) is limited in elderly acute myeloid leukemia (AML) patients. Therefore, combination strategies with targeted therapies are urgently needed. Here, we discover that priming with SGI-110 (guadecitabine), a next-generation HMA, sensitizes AML cells to ASTX660, a novel antagonist of cellular inhibitor of apoptosis protein 1 and 2 (cIAP1/2) and X-linked IAP (XIAP). Importantly, SGI-110 and ASTX660 synergistically induced cell death in a panel of AML cell lines as well as in primary AML samples while largely sparing normal CD34+ human progenitor cells, underlining the translational relevance of this combination. Unbiased transcriptome analysis revealed that SGI-110 alone or in combination with ASTX660 upregulated the expression of key regulators of both extrinsic and intrinsic apoptosis signaling pathways such as TNFRSF10B (DR5), FAS, and BAX. Individual knockdown of the death receptors TNFR1, DR5, and FAS significantly reduced SGI-110/ASTX660-mediated cell death, whereas blocking antibodies for tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) or FAS ligand (FASLG) failed to provide protection. Also, TNF alpha-blocking antibody Enbrel had little protective effect on SGI-110/ASTX660-induced cell death. Further, SGI-110 and ASTX660 acted in concert to promote cleavage of caspase-8 and BID, thereby providing a link between extrinsic and intrinsic apoptotic pathways. Consistently, sequential treatment with SGI-110 and ASTX660-triggered loss of mitochondrial membrane potential (MMP) and BAX activation which contributes to cell death, as BAX silencing significantly protected from SGI-110/ASTX660-mediated apoptosis. Together, these events culminated in the activation of caspases-3/-7, nuclear fragmentation, and cell death. In conclusion, SGI-110 and ASTX660 cooperatively induced apoptosis in AML cells by engaging extrinsic and intrinsic apoptosis pathways, highlighting the therapeutic potential of this combination for AML.