Synergistic antitumor effect of a penicillin derivative combined with thapsigargin in melanoma cells

BELLIZZI, YANINA; CORNIER PATRICIA; DELPICCOLO CARINA; MATA, ERNESTO G; BLANK VC; ROGUIN LEONOR P

JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY

SPRINGER

Lugar: Berlin; Año: 2022

0171-5216

Based on the concept that combination therapy is an auspicious strategy to increase therapeutic efficacy, and reduce dose, toxicity and unwanted side effects, the purpose of this study was to investigate the effect of TAP7f, a penicillin derivative previously characterized as a potent antitumor agent in melanoma cells, in combination with thapsigargin, an ER stress inducer. We demonstrated that the combination of TAP7f with thapsigargin synergistically inhibited the proliferation of human A375 and murine B16-F0 melanoma cells. Combination index values lower than 1 were obtained at different concentrations of TAP7f and thapsigargin, confirming the synergistic inhibitory effect of both drugs on melanoma cell growth. When non-inhibitory doses of each drug were simultaneously administered to C57BL/6J mice challenged with B16-F0 cells, a 60% reduction in tumor volumes was obtained in the combined group. An apoptotic response characterized by higher expression levels of the pro-apoptotic protein Bax, enhanced PARP-1 cleavage and the presence of active caspase 3 was observed in tumors from the combined treatment. In addition, significantly higher expression levels of GADD153/CHOP and ATF4 were found in tumors of mice treated with the two drugs with respect to each drug used alone, indicating the induction of a more potent ER stress response. No signs of tissue toxicity were observed in histological sections of different organs extracted from mice receiving the combination. In conclusion, the synergistic and effective antitumor action of TAP7f in combination with thapsigargin could be considered as a potential therapeutic strategy for melanoma treatment.