Previous studies presented that Gamitrinibs rapidly accumulate in tumor cell mitochondria, lead cells to apoptotic pathway in tumor cells.Thus Gamitrinibs are considered a series of promising drugs for cancer.However, a cell can die in different types e.g.apoptosis, necrosis or necroptosis, and autophagic cell death.In this study we aimed to further investigate the mechanisms and modes of cell death in G-TPP-treated Hep3B and U937 cell lines.It was observed that G-TPP killed U937 cells majorly in apoptotic pathway,and Hep3B cells majorly via activating caspase-independent necrosis and/or necroptosis with in part caspase-dependant apoptosis.Simultaneously, we observed G-TPP induced compensatory autophagy in Hep3B cell lines.Overexpression Bcl-2 significantly inhibited cell death in U937 cells, but not in Hep3B cells, contrarily, increase cell sensitiveness to G-TPP.We further probed it and found Bcl-2-Beclin 1 interaction in response to G-TPP by immunoprecipitation assay.However, silencing of beclin 1 failed to block accumulation of LC3 Ⅱ in Hep3B cells.Taken together, these data reveal that G-TPP induce cell death via apoptotic pathway in U937 cells, and a combination of death pathways, including necrosis and/or necroptosis and apoptosis Otherwise, G-TPP trigger Beclin 1-independant protective autophagy in Hep3B cells.Overexpression of Bcl-2 protein may be involved in other pathways to response to G-TPP and increase cells sensitive to G-TPP in Hep3B cells.The data are important for the therapeutic exploitation of necroptosis and/or necrosis as an alternative cell death program to bypass apoptosis resistance.