Targeting the Akt/PI3K/mTOR signaling pathway for complete eradication of keloid disease by sunitinib.
Apoptosis
; 27(11-12): 812-824, 2022 12.
Article
em En
| MEDLINE
| ID: mdl-35802302
ABSTRACT
Keloid disease is a nodular lesion, tumor-like but not cancerous, and characterized of excessive proliferation of fibroblasts and deposition of extracellular matrix (ECM) components. This condition often causes itching, pain and cosmetic disfigurement, significantly reducing patient quality of life. To date, no universally effective therapies are available, possibly due to inadequate understanding of keloid pathogenesis. As an oral small-molecule inhibitor of certain tyrosine kinase receptors, sunitinib has shown significant therapeutic effects in renal cell carcinoma (RCC) and gastrointestinal stromal tumor (GIST). However, it has never been tested if keloid therapy can be effective for the management of keloids. This study thus aims to explore the potential of sunitinib for keloid treatment. Keloid-derived fibroblasts (KFs) were successfully isolated and demonstrated proliferative advantage to normal skin-derived fibroblasts (NFs). Additionally, sunitinib showed specific cytotoxicity and inhibition of invasion, and induced cell cycle arrest and significant apoptosis in KFs. These effects were accompanied by complete suppression of ECM component expression, including collagen types 1 and 3, upregulation of autophagy-associated LC3B and significant suppression of the Akt/PI3K/mTOR pathway. Moreover, a keloid explant culture model was successfully established and used to test the therapeutic efficacy of sunitinib on keloid formation in nude mice. Sunitinib was found to induce complete regression of keloid explant fragments in nude mice, showing significantly higher therapeutic efficacy than the most commonly used intralesional drug triamcinolone acetonide (TAC). These data suggest that sunitinib effectively inhibits keloid development through suppression of the Akt/PI3K/mTOR pathway and thus can be potentially developed as a monotherapy or combination therapy for the effective treatment of keloid disease.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Contexto em Saúde:
1_ASSA2030
Base de dados:
MEDLINE
Assunto principal:
Queloide
Aspecto:
Patient_preference
Limite:
Animals
Idioma:
En
Revista:
Apoptosis
Ano de publicação:
2022
Tipo de documento:
Article