학술논문
The rational modulation of autophagy sensitizes colorectal cancer cells to 5-fluouracil and oxaliplatin.
Document Type
Academic Journal
Author
Baldasso-Zanon A; Programa de Pós-Graduação Ciências em Gastroenterologia e Hepatologia, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil.; Centro de Pesquisas Experimental, Laboratório de Biologia Celular e Molecular, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil.; Silva AO; Centro de Pesquisas Experimental, Laboratório de Biologia Celular e Molecular, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil.; Unidade Centro RS, Faculdade Estácio do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.; Franco N; Programa de Pós-Graduação Ciências em Gastroenterologia e Hepatologia, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil.; Centro de Pesquisas Experimental, Laboratório de Biologia Celular e Molecular, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil.; Picon RV; Programa de Pós-Graduação Ciências em Gastroenterologia e Hepatologia, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil.; Departamento de Medicina Interna, UFRGS, Porto Alegre, Rio Grande do Sul, Brazil.; Lenz G; Departamento de Biofísica, UFRGS, Porto Alegre, Rio Grande do Sul, Brazil.; Centro de Biotecnologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.; Lopez PLDC; Programa de Pós-Graduação Ciências em Gastroenterologia e Hepatologia, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil.; Centro de Pesquisas Experimental, Laboratório de Biologia Celular e Molecular, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil.; Filippi-Chiela EC; Programa de Pós-Graduação Ciências em Gastroenterologia e Hepatologia, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Rio Grande do Sul, Brazil.; Centro de Pesquisas Experimental, Laboratório de Biologia Celular e Molecular, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil.; Centro de Biotecnologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.; Departamento de Ciências Morfológicas, UFRGS, Porto Alegre, Rio Grande do Sul, Brazil.
Source
Publisher: Wiley-Liss Country of Publication: United States NLM ID: 8205768 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1097-4644 (Electronic) Linking ISSN: 07302312 NLM ISO Abbreviation: J Cell Biochem Subsets: MEDLINE
Subject
Language
English
Abstract
Colorectal cancer (CRC) is the third most common and deadliest cancer globally. Regimens using 5-fluorouracil (5FU) and Oxaliplatin (OXA) are the first-line treatment for CRC, but tumor recurrence is frequent. It is plausible to hypothesize that differential cellular responses are triggered after treatments depending on the genetic background of CRC cells and that the rational modulation of cell tolerance mechanisms like autophagy may reduce the regrowth of CRC cells. This study proposes investigating the cellular mechanisms triggered by CRC cells exposed to 5FU and OXA using a preclinical experimental design mimicking one cycle of the clinical regimen (i.e., 48 h of treatment repeated every 2 weeks). To test this, we treated CRC human cell lines HCT116 and HT29 with the 5FU and OXA, combined or not, for 48 h, followed by analysis for two additional weeks. Compared to single-drug treatments, the co-treatment reduced tumor cell regrowth, clonogenicity and stemness, phenotypes associated with tumor aggressiveness and poor prognosis in clinics. This effect was exerted by the induction of apoptosis and senescence only in the co-treatment. However, a week after treatment, cells that tolerated the treatment had high levels of autophagy features and restored the proliferative phenotype, resembling tumor recurrence. The pharmacologic suppression of early autophagy during its peak of occurrence, but not concomitant with chemotherapeutics, strongly reduced cell regrowth. Overall, our experimental model provides new insights into the cellular mechanisms that underlie the response and tolerance of CRC cells to 5FU and OXA, suggesting optimized, time-specific autophagy inhibition as a new avenue for improving the efficacy of current treatments.
(© 2024 Wiley Periodicals LLC.)
(© 2024 Wiley Periodicals LLC.)