Conventional cytotoxic drugs preferentially eliminate differentiated
cancer cells but spare relatively more resistant stem-like
cancer cells capable to initiate recurrence. Due to
cancer cell plasticity, the stem-like phenotype can be also acquired by
cancer cells refractory to treatment with cytotoxic drugs. We investigated whether drugs inhibiting
receptor tyrosine kinases could be used to target human
colon cancer cells initiating
cancer regrowth following conventional cytotoxic treatment. The moderately differentiated cell line HT-29 and poorly differentiated cell line HCT-116 were exposed to
5-fluorouracil (5-FU). Cells that resisted the exposure to
5-FU were subsequently treated with
imatinib or
sunitinib. Both drugs reduced clonogenicity of 5-FU-refractory cells under normoxic and hypoxic culture conditions. The expression of numerous stemness-related genes was upregulated in
cancer cells following the exposure to
5-FU, and remained at a high level in 5-FU-refractory cells undergoing renewal under normoxia, but decreased spontaneously under
hypoxia.
Imatinib downregulated the expression of stemness-related genes in cells undergoing renewal under normoxia. A combination of
imatinib with
PRI-2191, an analogue of
1,25-dihydroxyvitamin D3, downregulated stemness-related genes in HCT-116/5-FU cells more efficiently than
imatinib alone. A synthetic analogue of
1,25-dihydroxyvitamin D2 (PRI-1906) abolished the effect of
imatinib on gene expression in HCT-116/5-FU cells undergoing renewal under normoxia.
Sunitinib promoted shift of phenotype of HT-29/5-FU cells undergoing renewal toward stem-like one. It suggests that the phenotype shift toward stemness induced by sequential
sunitinib treatment following
5-FU treatment could increase a risk of
cancer recurrence. In contrast to
sunitinib,
imatinib could be used both to interfere with
cancer regrowth after conventional
chemotherapy and to downregulate the expression of stemness-related genes in residual
colon cancer cells capable to initiate
cancer recurrence. The findings suggest that
imatinib could also be combined with
vitamin D analogue
PRI-2191 to prevent recurrence more efficiently than
imatinib alone and to compensate for
vitamin D deficiency resulting from
imatinib treatment.