p53-Reactivating small molecules induce apoptosis and enhance chemotherapeutic cytotoxicity in head and neck squamous cell carcinoma.
We evaluate whether p53-reactivating (p53RA) small molecules induce p53-dependent apoptosis in head and neck squamous cell carcinoma (HNSCC), a question that has not been previously addressed in head and neck cancer. PRIMA-1, CP-31398, RITA, and nutlin-3 were tested in four human HNSCC cell lines differing in TP53 status. Cell growth, viability, cell cycle progression, and apoptosis after treatment with p53RA small molecules individually or in combination with chemotherapeutic agents were assessed. Prominent p53 reactivation was observed in mutant TP53-bearing tumor cell lines treated with PRIMA-1 or CP-31398, and in wild-type TP53-bearing cell lines treated with nutlin-3. Cell-cycle arrest and apoptosis induced by p53RA small molecules were associated with upregulation of p21 and BAX, and cleavage of caspase-3. Nutlin-3 showed maximal growth suppression in tumor cells showing MDM2-dependent p53 degradation. High-dose treatment with p53RA small molecules also induced apoptosis in cell lines independent of p53 or MDM2 expression. In combination therapy, p53RA small molecules enhanced the anti-tumor activity of cisplatin, 5-fluorouracil, paclitaxel, and erlotinib against HNSCC cells. The p53RA small molecules effectively restored p53 tumor-suppressive function in HNSCCs with mutant or wild-type TP53. The p53RA agents may be clinically useful against HNSCC, in combination with chemotherapeutic drugs.
Department of Otolaryngology - Head and Neck Surgery, Johns Hopkins University School of Medicine, 601 N. Caroline St., JHOC 6221, Baltimore, MD, USA.
Jong-Lyel
JL
Roh
Sung Koo
SK
Kang
Il
I
Minn
Joseph A
JA
Califano
David
D
Sidransky
Wayne M
WM
Koch
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003131:Combined Modality Therapy / Q000379:methods; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005663:Furans / Q000494:pharmacology; D015316:Genetic Therapy / Q000379:methods; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D010879:Piperazines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011812:Quinuclidines / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D000970:Antineoplastic Agents; D005663:Furans; D007093:Imidazoles; C118989:NSC 652287; D010879:Piperazines; D011743:Pyrimidines; D011812:Quinuclidines; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; C402665:CP 31398; C533410:eprenetapopt