Identification of a novel senolytic agent, navitoclax, targeting the Bcl‐2 family of anti‐apoptotic factors

• DOI: 10.1111/acel.12445
• Publication Date: 2015-12-29T13:28:47Z
• Authors: Yi Zhu; Tamara Tchkonia; Heike Fuhrmann‐St...; Haiming M. Dai; Yuanyuan Y. Ling; Michael B. Stout; Tamar Pirtskhalava; Nino Giorgadze; Kurt O. Johnson; Cory B. Giles; Jonathan D. Wren; Laura J. Niedernh...; Paul D. Robbins; James L. Kirkland
• Keywords: Identification; Bcl-2 Family

Clearing senescent cells extends healthspan in mice. Using a hypothesis-driven bioinformatics-based approach, we recently identified pro-survival pathways human that contribute to their resistance apoptosis. This led identification of dasatinib (D) and quercetin (Q) as senolytics, agents target some these induce apoptosis preferentially cells. Among other regulators was Bcl-xl. Here, tested whether the Bcl-2 family inhibitors, navitoclax (N) TW-37 (T), are senolytic. Like D Q, N is senolytic some, but not all types cells: reduced viability umbilical vein epithelial (HUVECs), IMR90 lung fibroblasts, murine embryonic fibroblasts (MEFs), primary preadipocytes, consistent with our previous finding Bcl-xl siRNA HUVECs, preadipocytes. In contrast, T had little activity. targets Bcl-2, Bcl-xl, Bcl-w, while Mcl-1. The combination Bcl-w siRNAs HUVECs cells, Mcl-1 not. Susceptibility correlated patterns member proteins different has been found predicting response cancers N. Thus, acts potentially predictable cell type-restricted manner. hypothesis-driven, approach used discover can be extended increase repertoire drugs, including additional type-specific agents.