Differential interference of vitamin D analogs PRI-1906, PRI-2191, and PRI-2205 with the renewal of human colon cancer cells refractory to treatment with 5-fluorouracil.
This study was aimed to determine whether hypocalcemic analogs of active forms of vitamins D modulate expression of genes related to stem-like phenotype in colon cancer cell lines HT-29 and HCT-116 undergoing renewal after the treatment with 5-fluorouracil (5-FU). Both lines express vitamin D receptor, but differ in differentiation stage and vitamin D sensitivity. Cells that resisted the 5-FU exposure were treated with synthetic analog of 1,25-dihydroxyvitamin D2 (PRI-1906) and analogs of 1,25-dihydroxyvitamin D3 (PRI-2191 and PRI-2205). Proliferative activity was more profoundly affected by vitamin D analogs in HT-29/5-FU than in HCT-116/5-FU cells. In HT-29/5-FU cells, analogs PRI-1906 and PRI-2191 downregulated the expression of genes related to survival, re-growth, and invasiveness during renewal, while PRI-2205 increased expression of genes related to differentiation only. In HCT-116/5-FU cells, PRI-2191 decreased the expression of stemness- and angiogenesis-related genes, whereas PRI-1906 augmented their expression. The effects in HCT-116/5-FU cells were observed at higher concentrations of the analogs than those used for HT-29/5-FU cells. Out of the series of analogs studied, PRI-2191 might be used to counteract the renewal of both moderately and poorly differentiated cancer cells following conventional treatment.
Department of Immunology, Maria Skłodowska-Curie Memorial Cancer Centre and Institute of Oncology, 5 WK Roentgen Str., 02-781, Warszawa, Poland.
Agnieszka
A
Kotlarz
Department of Immunology, Maria Skłodowska-Curie Memorial Cancer Centre and Institute of Oncology, 5 WK Roentgen Str., 02-781, Warszawa, Poland.
Małgorzata
M
Przybyszewska
Department of Immunology, Maria Skłodowska-Curie Memorial Cancer Centre and Institute of Oncology, 5 WK Roentgen Str., 02-781, Warszawa, Poland.
Paweł
P
Swoboda
Department of Immunology, Maria Skłodowska-Curie Memorial Cancer Centre and Institute of Oncology, 5 WK Roentgen Str., 02-781, Warszawa, Poland. joannam@coi.waw.pl.
Joanna
J
Miłoszewska
Department of Immunology, Maria Skłodowska-Curie Memorial Cancer Centre and Institute of Oncology, 5 WK Roentgen Str., 02-781, Warszawa, Poland.
Monika Anna
MA
Grygorowicz
Pharmaceutical Research Institute, 8 Rydygiera Str., 01-793, Warszawa, Poland.
Andrzej
A
Kutner
Department of Immunology, Maria Skłodowska-Curie Memorial Cancer Centre and Institute of Oncology, 5 WK Roentgen Str., 02-781, Warszawa, Poland.
Sergiusz
S
Markowicz
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000494:pharmacology; D000066673:Cell Self Renewal / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D004100:Dihydroxycholecalciferols / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D058750:Epithelial-Mesenchymal Transition; D004872:Ergocalciferols / Q000494:pharmacology*; D005472:Fluorouracil / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000502:physiology; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology
D000964:Antimetabolites, Antineoplastic; D004100:Dihydroxycholecalciferols; D004872:Ergocalciferols; C055085:calcipotriene; C003564:1,25-dihydroxyergocalciferol; C023850:1 alpha,24-dihydroxyvitamin D3; D002117:Calcitriol; D005472:Fluorouracil
Cancer stem cells; Colorectal cancer; EMT; Vitamin D analogs