NOTCH1 inhibition enhances the efficacy of conventional chemotherapeutic agents by targeting head neck cancer stem cell.
Cancer stem cells (CSCs) are considered responsible for tumor initiation and chemoresistance. This study was aimed to investigate the possibility of targeting head neck squamous cell carcinoma (HNSCC) by NOTCH1 pathway inhibition and explore the synergistic effect of combining NOTCH inhibition with conventional chemotherapy. NOTCH1/HES1 elevation was found in human HNSCC, especially in tissue post chemotherapy and lymph node metastasis, which is correlated with CSCs markers. NOTCH1 inhibitor DAPT (GSI-IX) significantly reduces CSCs population and tumor self-renewal ability in vitro and in vivo. Flow cytometry analysis showed that NOTCH1 inhibition reduces CSCs frequency either alone or in combination with chemotherapeutic agents, namely, cisplatin, docetaxel, and 5-fluorouracil. The combined strategy of NOTCH1 blockade and chemotherapy synergistically attenuated chemotherapy-enriched CSC population, promising a potential therapeutic exploitation in future clinical trial.
The State Key Laboratory Breeding Base of Basic Science of Stomatology &Key Laboratory of Oral Biomedicine, Ministry of Education, Wuhan, China.
Zhi-Li
ZL
Zhao
The State Key Laboratory Breeding Base of Basic Science of Stomatology &Key Laboratory of Oral Biomedicine, Ministry of Education, Wuhan, China.
Lu
L
Zhang
The State Key Laboratory Breeding Base of Basic Science of Stomatology &Key Laboratory of Oral Biomedicine, Ministry of Education, Wuhan, China.
Cong-Fa
CF
Huang
The State Key Laboratory Breeding Base of Basic Science of Stomatology &Key Laboratory of Oral Biomedicine, Ministry of Education, Wuhan, China.
Si-Rui
SR
Ma
The State Key Laboratory Breeding Base of Basic Science of Stomatology &Key Laboratory of Oral Biomedicine, Ministry of Education, Wuhan, China.
Lin-Lin
LL
Bu
The State Key Laboratory Breeding Base of Basic Science of Stomatology &Key Laboratory of Oral Biomedicine, Ministry of Education, Wuhan, China.
Jian-Feng
JF
Liu
The State Key Laboratory Breeding Base of Basic Science of Stomatology &Key Laboratory of Oral Biomedicine, Ministry of Education, Wuhan, China.
Guang-Tao
GT
Yu
Department of Oral Maxillofacial-Head Neck Oncology, School and Hospital of Stomatology, Wuhan University, Wuhan, China.
Bing
B
Liu
Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD USA.
J Silvio
JS
Gutkind
Functional Genomics Section, Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD USA.
Ashok B
AB
Kulkarni
Department of Oral Maxillofacial-Head Neck Oncology, School and Hospital of Stomatology, Wuhan University, Wuhan, China.
Wen-Feng
WF
Zhang
The State Key Laboratory Breeding Base of Basic Science of Stomatology &Key Laboratory of Oral Biomedicine, Ministry of Education, Wuhan, China.|Department of Oral Maxillofacial-Head Neck Oncology, School and Hospital of Stomatology, Wuhan University, Wuhan, China.|Functional Genomics Section, Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD USA.
Zhi-Jun
ZJ
Sun
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D045744:Cell Line, Tumor; D000066673:Cell Self Renewal / Q000187:drug effects; D002945:Cisplatin / Q000627:therapeutic use; D003959:Diamines / Q000494:pharmacology / Q000627:therapeutic use*; D000077143:Docetaxel; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D006258:Head and Neck Neoplasms / Q000188:drug therapy*; D006801:Humans; D008207:Lymphatic Metastasis; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000502:physiology; D034741:RNA, Small Interfering / Q000235:genetics; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D043823:Taxoids / Q000627:therapeutic use; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
C000612000:24-diamino-5-phenylthiazole; D003959:Diamines; C497761:NOTCH1 protein, human; D034741:RNA, Small Interfering; D051881:Receptor, Notch1; D043823:Taxoids; D013844:Thiazoles; D000077143:Docetaxel; D002945:Cisplatin; D005472:Fluorouracil