Clearance of therapy‐induced senescent tumor cells by the senolytic ABT‐263 via interference with BCL‐XL–BAX interaction. Issue 10 (5th August 2020)

• Record Type: Journal Article
• Authors: Saleh, Tareq; Carpenter, Valerie J.; Tyutyunyk‐Massey, Liliya; Murray, Graeme; Leverson, Joel D.; Souers, Andrew J.; Alotaibi, Moureq R.; Faber, Anthony C.; Reed, Jason; Harada, Hisashi; Gewirtz, David A.
• Is Part Of: Molecular oncology. Volume 14:Issue 10(2020)
• Page Start: 2504
• Page End: 2519
• Publication Date: 2020-08-05
• Subjects: ABT‐263 -- BCL‐XL -- chemotherapy -- radiation -- senescence -- senolytic; Cancer -- Molecular aspects -- Periodicals; 616.994005
• DOI: 10.1002/1878-0261.12761
• Languages: English
• ISSNs: 1574-7891

Abstract

Abstract : Tumor cells undergo senescence in response to both conventional and targeted cancer therapies. The induction of senescence in response to cancer therapy can contribute to unfavorable patient outcomes, potentially including disease relapse. This possibiliy is supported by our findings that tumor cells induced into senescence by doxorubicin or etoposide can give rise to viable tumors in vivo . We further demonstrate sensitivity of these senescent tumor cells to the senolytic ABT‐263 (navitoclax), therefore providing a "two‐hit" approach to eliminate senescent tumor cells that persist after exposure to chemotherapy or radiation. The sequential combination of therapy‐induced senescence and ABT‐263 could shift the response to therapy toward apoptosis by interfering with the interaction between BCL‐XL and BAX. The administration of ABT‐263 after either etoposide or doxorubicin also resulted in marked, prolonged tumor suppression in tumor‐bearing animals. These findings support the premise that senolytic therapy following conventional cancer therapy may improve therapeutic outcomes and delay disease recurrence. Abstract : Senescent tumor cells can be selectively eliminated by the BH3 mimetic, ABT‐263 (navitoclax), via senolysis. We show that ABT‐263 inhibits the interaction between anti‐apoptotic BCL‐2 family member, BCL‐XL, and pro‐apoptotic effector, BAX. This results in senescent tumor cell death in vitro and reduced tumor volume in vivo . This work highlights the utilization of senolytic agents to enhance efficacy of anticancer therapy.