Abstract
Cancer cells develop tactics to circumvent the interventions by desensitizing themselves to interventions. The principle route of desensitization includes activation of survival pathways (e.g. NF-kB, PARP) and downregulation of cell death pathways (e.g. CD95, ASK1). As a result, it requires high dose of therapy to induce cell death which, in turn damages normal cells through the collateral effects. Methods are needed to sensitize the low and non-responsive resistant tumor cells in order to evoke a better response from the current treatments. Current treatments including chemotherapy can induce cell death only in bulk cancer cells sparing low-responsive and resistant tumor cells. Here we report a novel tumor sensitizer derived from the natural Vitamin E analogue (AMP-001). The drug design is based on a novel “A priori activation of apoptosis pathways of tumor technology (AAAPT) which is designed to activate cell death pathways and inhibit survival pathways simultaneously. It involves an inbuilt targeting vector which targets tumor specific Cathepsin B, overexpressed by many cancers including gastric cancer. Our results indicate that AMP-001 sensitizes gastric cancer cells which resulted in expanding the therapeutic index of front-line chemotherapy doxorubicin both in vitro and in vivo nude mouse model. The synergy between AMP-001 and doxorubicin could pave a new pathway to use AMP-001 as a neoadjuvant to chemotherapy to achieve a better efficacy and reduced off-target toxicity.