RT Journal Article
SR Electronic
T1 <strong>Senolytic-mediated elimination of head and neck tumor cells </strong><strong>induced into senescence by cisplatin</strong>
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP MOLPHARM-AR-2021-000354
DO 10.1124/molpharm.121.000354
A1 Ahmadinejad, Fereshteh
A1 Bos, Tasia
A1 Hu, Bin
A1 Britt, Erin
A1 Koblinski, Jennifer
A1 Souers, Andrew J
A1 Leverson, Joel D.
A1 Faber, Anthony C.
A1 Gewirtz, David A.
A1 Harada, Hisashi
YR 2021
UL http://molpharm.aspetjournals.org/content/early/2021/12/14/molpharm.121.000354.abstract
AB Therapeutic outcomes achieved in head and neck squamous cell carcinoma (HNSCC) patients by concurrent cisplatin-based chemoradiotherapy initially reflect both tumor regression and tumor stasis. However, local and distant metastasis and disease relapse are common in HNSCC patients. In the current work, we demonstrate that cisplatin treatment induces senescence in head and neck cancer models from which tumor cells can escape both in vitro and in vivo. We further establish the effectiveness of the senolytic, ABT-263 (Navitoclax), in elimination of senescent tumor cells after cisplatin treatment. Additionally, we show that ABT-263 interferes with the interaction between BCL-XL and BAX, anti- and pro-apoptotic proteins, respectively, followed by BAX activation. Our in vivo studies also confirm senescence induction in tumor cells by cisplatin, and the promotion of apoptosis coupled with a significant decrease in tumor size after sequential treatment with ABT-263. These results support the premise that senolytic agents could be utilized to eliminate residual senescent tumor cells after chemotherapy and thereby potentially delay disease recurrence in head and neck cancer patients. Significance Statement Disease recurrence is the most common cause of death in head and neck cancer patients. BCL-XL inhibitors such as ABT-263 (Navitoclax) have the capacity to be used in combination with cisplatin in head and neck cancer patients to eliminate senescent cells and possibly prevent disease relapse.