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Sunitinib promotes apoptosis via p38 MAPK activation and STAT3 downregulation in oral keratinocytes.
Fukada, Shohei; Ohta, Kouji; Sakuma, Miyuki; Akagi, Misaki; Kato, Hiroki; Naruse, Takako; Nakagawa, Takayuki; Shigeishi, Hideo; Nishi, Hiromi; Takechi, Masaaki; Aikawa, Tomonao.
Affiliation
  • Fukada S; Department of Oral and Maxillofacial Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
  • Ohta K; Department of Public Oral Health, Program of Oral Health Sciences, Hiroshima University, Hiroshima, Japan.
  • Sakuma M; Department of Oral and Maxillofacial Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
  • Akagi M; Department of Oral and Maxillofacial Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
  • Kato H; Department of Dentistry, Oral and Maxillofacial Surgery, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Kure, Japan.
  • Naruse T; Department of Oral and Maxillofacial Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
  • Nakagawa T; Department of Oral and Maxillofacial Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
  • Shigeishi H; Department of Public Oral Health, Program of Oral Health Sciences, Hiroshima University, Hiroshima, Japan.
  • Nishi H; Department of General Dentistry, Hiroshima University Hospital, Hiroshima, Japan.
  • Takechi M; Department of Dentistry, Oral and Maxillofacial Surgery, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Kure, Japan.
  • Aikawa T; Department of Oral and Maxillofacial Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
Oral Dis ; 2022 Nov 29.
Article in En | MEDLINE | ID: mdl-36447393
ABSTRACT

OBJECTIVE:

Sunitinib, a targeted cancer drug, inhibits tyrosine kinases receptors and is widely used as first-line treatment for metastatic renal cell carcinoma. Patients undergoing chemotherapy with sunitinib frequently have oral mucosal complications, such as oral stomatitis, though cytotoxic effects of the drug on oral keratinocytes remain unknown.

METHODS:

The effects of sunitinib on immortalized oral keratinocytes, RT7 cells, in regard to cell injury and apoptosis, as well as apoptosis-mediated signaling pathways were investigated.

RESULTS:

Sunitinib treatment caused a significant increase in lactate dehydrogenase (LDH) in RT7 cells and primary oral keratinocytes. Additionally, the drug induced apoptosis-related events, such as DNA fragmentation, decreased anti-apoptotic Bcl-2 protein expression, and induction of cleaved PARP and caspase 3/9 in RT7 cells. Furthermore, phosphorylation of p38 MAPK, but not of ERK or JNK, was increased. On the contrary, constitutive phosphorylated STAT3 was decreased by sunitinib treatment, which was recovered by exposure to SB203580, a p38 MAPK inhibitor. Finally, SB203580 was found to reduce sunitinib-induced cell injury and apoptosis.

CONCLUSION:

The present results indicate that sunitinib promotes cell injury and apoptosis in oral keratinocytes via p38 activation and STAT3 downregulation. Sunitinib-mediated oral complications may be associated with cytotoxic effects of the drug on oral keratinocytes.
Key words

Full text: 1 Collection: 01-internacional Database: MEDLINE Language: En Journal: Oral Dis Journal subject: ODONTOLOGIA Year: 2022 Document type: Article Affiliation country: Japan

Full text: 1 Collection: 01-internacional Database: MEDLINE Language: En Journal: Oral Dis Journal subject: ODONTOLOGIA Year: 2022 Document type: Article Affiliation country: Japan