The PARP inhibitor olaparib potentiates the effect of the DNA damaging agent doxorubicin in osteosarcoma

Abstract

Background: PARP1 facilitates the recovery of DNA-damaged cells by recruiting DNA damage response molecules such as gamma H2AX and BRCA1/2, and plays a role in resistance to antitumor therapies. Therefore, PARP inhibition being evaluated as an anti-cancer therapy. However, there are limited studies regrading PARP inhibition in osteosarcoma. Methods: We evaluated the expression of DNA damage response molecules in 35 human osteosarcomas and investigated the effects of co-treatment of the PARP inhibitor, olaparib, and doxorubicin in osteosarcoma cells. Results: The expression patterns of PARP1, gamma H2AX, BRCA1, and BRCA2 were significantly associated with shorter survival of osteosarcoma patients. In osteosarcoma cells, knock-down of PARP1 and treatment of olaparib significantly inhibited proliferation of cells and induced apoptosis. Moreover, the anti-tumor effect was more. significant with co-treatment of olaparib and doxorubicin in vitro and in vivo. Conclusions: This study suggests that combined use of a PARP inhibitor with doxorubicin, a DNA damaging agent, might be effective in the treatment of osteosarcoma patients, especially in the poor-piognostic subgroups of osteosarcoma expressing PARP1, gamma H2AX, or BRCA1/2.