Acquired resistance to the anticancer drug paclitaxel is associated with induction of cytochrome P450 2C8.
BACKGROUND
We have previously shown that human colorectal cancer tissue is able to inactivate the anticancer drug paclitaxel through cytochrome P450 (CYP)2C8 and CYP3A4 metabolisms. The aim of this study was to evaluate whether changes in the expression levels of genes coding for such enzymes are related to anticancer drug resistance after long-term exposure to the drug.


METHODS
Human colorectal cancer cells (Caco-2) that are sensitive to paclitaxel were exposed to increasing concentrations of the drug from 0-250 nM during one year, in order to select paclitaxel-resistant cells. Subsequently, we compared the sensitivity to paclitaxel and the extent of expression of the CYP2C8, CYP3A4 and CYP3A5 genes in original and resistant cells.


RESULTS
Resistant cancer cells displayed a 246-fold increased lethal dose (LD)50 to paclitaxel (p < 0.004) as compared with original cancer cells. A 4.4-fold (p = 0.005) enhancement of CYP2C8 expression and a 5.6-fold (p = 0.001) increase of multidrug resistance (MDR)1 expression was observed in resistant cells exposed to paclitaxel. When paclitaxel was removed from the culture medium, CYP2C8, but not MDR1 expression, reverted to basal levels and the resistance to paclitaxel decreased 3.2-fold (p = 0.005). No major changes in the expression levels of CYP3A4 and CYP3A5 were observed.


CONCLUSIONS
Caco-2 cells are capable of increasing the expression levels of CYP2C8 as a response to long-term exposure to paclitaxel. This study provides evidence for a mechanism of acquired resistance to anticancer therapy based on the induction of anticancer-metabolizing enzymes.
García-Martín
Elena
E
University of Extremadura, Biochemistry & Molecular Biology & Genetics, Avda. de Elvas s/n, 06071, Badajoz, Spain.
Pizarro
Rosa M
RM
Martínez
Carmen
C
Gutierrez-Martín
Yolanda
Y
Pérez
Gabriela
G
Jover
Ramiro
R
Agúndez
José Ag
JA
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis* / Q000235:genetics*; D001483:Base Sequence; D018938:Caco-2 Cells; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D065727:Cytochrome P-450 CYP2C8; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004790:Enzyme Induction / Q000187:drug effects / Q000235:genetics; D005472:Fluorouracil / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D019450:Genes, MDR; D006801:Humans; D007928:Lethal Dose 50; D017239:Paclitaxel / Q000494:pharmacology*; D010597:Pharmacogenetics
D000972:Antineoplastic Agents, Phytogenic; D018076:DNA, Complementary; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; C510164:CYP3A5 protein, human; D065727:Cytochrome P-450 CYP2C8; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D017239:Paclitaxel; D005472:Fluorouracil