Drug resistance becomes a formidable challenge against effective
cancer therapy. Defective apoptosis in
cancer cells is a key factor responsible for chemoresistance or radioresistance. Promoting apoptosis is an important method to sensitize the resistant cells, thereby achieving successful treatment for MDR
cancer. We present a strategy of codelivery of apoptotic AVPI
peptide and p53
DNA as apoptosis-induction adjuvant
therapy for combating the resistant
breast cancer. AVPI tetrapeptide is poorly cell-permeable, thereby with very limited value for
therapeutic use. Cell-penetrating chimeric AVPI derivative was developed by modification with an octa-
arginine sequence (R8). The AVPIR8 is able to not only efficiently penetrate into
tumor cells but also work as a vector for gene delivery by forming nanocomplexes based on its cationic R8 moiety. The combination of AVPIR8/p53
DNA was selected for targeting apoptotic pathways, thereby sensitizing the
cancer cells to chemotherapeutics. The anti-MDR effect was demonstrated both in vitro and in vivo. The synergistic use of AVPIR8/p53 significantly increased the sensitivity of the resistant
tumor cells to the
cytotoxic agent doxorubicin by inducing apoptosis, as demonstrated in the cellular studies. Importantly, the treatment improvement was also observed in the animal studies with resistant
breast tumor model. Coadministration of AVPIR8/p53 enabled a full arrest of
tumor growth combined with a reduced DOX dose, yielding a productive and safe
cancer treatment.