ABT-737 Synergizes with Chemotherapy to Kill Head and Neck Squamous Cell Carcinoma Cells via a Noxa-Mediated Pathway

• Published in: Molecular pharmacology Vol. 75; no. 5; pp. 1231 - 1239
• Main Authors: Li, Rongxiu, Zang, Yan, Li, Changyou, Patel, Neil S, Grandis, Jennifer R, Johnson, Daniel E
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics 01.05.2009
• Subjects: Antineoplastic Agents - pharmacology; Apoptosis - drug effects; bcl-X Protein - antagonists & inhibitors; Biphenyl Compounds - pharmacology; Boronic Acids - pharmacology; Bortezomib; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - pathology; Cell Line, Tumor; Cisplatin - pharmacology; Drug Synergism; Head and Neck Neoplasms - drug therapy; Head and Neck Neoplasms - pathology; Humans; Myeloid Cell Leukemia Sequence 1 Protein; Nitrophenols - pharmacology; Piperazines - pharmacology; Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - physiology; Pyrazines - pharmacology; Signal Transduction; Sulfonamides - pharmacology
• ISSN: 0026-895X; 1521-0111
• DOI: 10.1124/mol.108.052969

Overexpression of Bcl-X L , an antiapoptotic Bcl-2 family member, occurs in a majority of head and neck squamous cell carcinomas (HNSCCs) and correlates with chemotherapy resistance in this disease. Overexpression of Bcl-2 is also observed in HNSCC, albeit less frequently. We have previously shown that peptides derived from the BH3 domains of proapoptotic proteins can be used to target Bcl-X L and Bcl-2 in HNSCC cells, promoting apoptosis. In this report, we examined the impact of ABT-737 (for structure, see ), a potent small-molecule inhibitor of Bcl-X L and Bcl-2, on HNSCC cells. As a single agent, ABT-737 was largely ineffective at promoting HNSCC cell death. By contrast, ABT-737 strongly synergized with the chemotherapy drugs cisplatin and etoposide to promote HNSCC cell death and loss of clonogenic survival. Synergism between ABT-737 and chemotherapy was associated with synergistic activation of caspase-3 and cleavage of poly(ADP-ribose) polymerase. Treatment with ABT-737 plus chemotherapy resulted in dramatic up-regulation of proapoptotic Noxa protein, and small interfering RNA (siRNA)-mediated inhibition of Noxa up-regulation partially attenuated cell death by the synergistic combination. Treatment with cisplatin or etoposide, alone or in combination with ABT-737, resulted in substantial down-regulation of Mcl-1L, a known inhibitor of ABT-737 action. Further down-regulation of Mcl-1L using siRNA failed to enhance killing by the cisplatin/ABT-737 synergistic combination, indicating that chemotherapy treatment of HNSCC cells is sufficient to remove this impediment to ABT-737. Together, our results demonstrate potent synergy between ABT-737 and chemotherapy drugs in the killing of HNSCC cells and reveal an important role for Noxa in mediating synergism by these agents.