Rational Drug Design of Targeted and Enzyme-Cleavable Vitamin E Analogs as a Neoadjuvant to Chemotherapy: In Vitro and In Vivo Evaluation on Reduction of the Cardiotoxicity Side Effect of Doxorubicin

Traditional drug design focuses on specific biological targets where specific receptors or biomarkers are overexpressed by cancer cells. Cancer cells circumvent the interventions by activating survival pathways and/or downregulating cell death pathways for their survival. A priori activation of apoptosis pathways of tumor (AAAPT) is a novel tumor-sensitizing technology that sensitizes tumor cells that are not responding well to the current treatments by targeting specific survival pathways involved in the desensitization of tumor cells and tries to revive them selectively in cancer cells, sparing normal cells. Several vitamin E derivatives (AMP-001, AMP-002, AMP-003, and AMP-004) were synthesized, characterized, and studied for their anti-tumorigenic properties and their synergistic potential with the standard chemotherapy doxorubicin in various cancer cells including brain cancer stem cells in vitro. Preliminary studies revealed that AAAPT drugs (a) reduced the invasive potential of brain tumor stem cells, (b) synergized with Federal Drug Application-approved doxorubicin, and (c) enhanced the therapeutic index of doxorubicin in the triple-negative breast cancer tumor rat model, preserving the ventricular function compared to cardiotoxic doxorubicin alone at therapeutic dose. The AAAPT approach has the advantage of inhibiting survival pathways and activating cell death pathways selectively in cancer cells by using targeting, linkers cleavable by tumor-specific Cathepsin B, and PEGylation technology to enhance the bioavailability. We propose AAAPT drugs as a neoadjuvant to chemotherapy and not as stand-alone therapy, which is shown to be effective in expanding the therapeutic index of doxorubicin and making it work at lower doses.