Pharmacological inhibition of BCL-2 with the FDA-approved drug venetoclax impairs longitudinal bone growth

Abstract

Abstract Treatment-related skeletal complications are common in childhood cancer patients and survivors. Venetoclax is a BCL-2 inhibitor that has shown efficacy in hematological malignancies in adults and is being investigated in pediatric cancer clinical trials as a promising therapeutic modality. Venetoclax triggers cell death in cancer cells, but whether it exerts similar effects in normal bone cells, is unknown. Chondrogenic ATDC5 cells, E20 fetal rat metatarsal bones, and human growth plate biopsies were treated with different concentrations of venetoclax. Female NMRI nu/nu mice were treated with venetoclax or vehicle for 15 days. Mice were X-rayed at baseline and at the end of the experiment to assess longitudinal bone growth and body weight was monitored throughout the study. Histomorphometric and immunohistochemical analyses were performed to evaluate treatment effects on the growth plate cartilage. Venetoclax decreased the viability of chondrocytes and impaired the growth of ex vivo cultured metatarsals while reducing the height of the resting/proliferative zone and the hypertrophic cell size. When tested in vivo, venetoclax suppressed bone growth and reduced growth plate height. Our experimental data suggest that venetoclax directly targets growth plate chondrocytes suppressing bone growth and we, therefore, encourage careful monitoring of longitudinal bone growth if treating growing children with venetoclax.