Targeting mitochondrial bioenergetics by combination treatment with imatinib and dichloroacetate in human erythroleukemic K562 and colorectal HCT116 cancer cells.
Int J Oncol
; 64(4)2024 04.
Article
en En
| MEDLINE
| ID: mdl-38426621
ABSTRACT
Tumor malignant cells are characterized by dysregulation of mitochondrial bioenergetics due to the 'Warburg effect'. In the present study, this metabolic imbalance was explored as a potential target for novel cancer chemotherapy. Imatinib (IM) downregulates the expression levels of SCΟ2 and FRATAXIN (FXN) genes involved in the hemedependent cytochrome c oxidase biosynthesis and assembly pathway in human erythroleukemic IMsensitive K562 chronic myeloid leukemia cells (K562). In the present study, it was investigated whether the treatment of cancer cells with IM (an inhibitor of oxidative phosphorylation) separately, or together with dichloroacetate (DCA) (an inhibitor of glycolysis), can inhibit cell proliferation or cause death. Human K562 and IMchemoresistant K562 chronic myeloid leukemia cells (K562R), as well as human colorectal carcinoma cells HCT116 (+/+p53) and (/p53, with double TP53 knock-in disruptions), were employed. Treatments of these cells with either IM (1 or 2 µM) and/or DCA (4 mΜ) were also assessed for the levels of several process biomarkers including SCO2, FXN, lactate dehydrogenase A, glyceraldehyde3phosphate dehydrogenase, pyruvate kinase M2, hypoxia inducing factor1a, heme oxygenase1, NFκB, stem cell factor and vascular endothelial growth factor via western blot analysis. Computational network biology models were also applied to reveal the connections between the ten proteins examined. Combination treatment of IM with DCA caused extensive cell death (>75%) in K562 and considerable (>45%) in HCT116 (+/+p53) cultures, but less in K562R and HCT116 (/p53), with the latter deficient in full length p53 protein. Such treatment, markedly reduced reactive oxygen species levels, as measured by flowcytometry, in K562 cells and affected the oxidative phosphorylation and glycolytic biomarkers in all lines examined. These findings indicated, that targeting of cancer mitochondrial bioenergetics with such a combination treatment was very effective, although chemoresistance to IM in leukemia and the absence of a full length p53 in colorectal cells affected its impact.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Neoplasias Colorrectales
/
Leucemia Mielógena Crónica BCR-ABL Positiva
/
Leucemia Eritroblástica Aguda
Límite:
Humans
Idioma:
En
Revista:
Int J Oncol
/
Int.j. oncol
/
International journal of oncology
Asunto de la revista:
NEOPLASIAS
Año:
2024
Tipo del documento:
Article
País de afiliación:
Grecia