Role of caspases in 5-FU and selenium-induced growth inhibition of colorectal cancer cells.
BACKGROUND
The mechanisms that could explain the poor sensitivity to 5-FU in certain colorectal cancer (CRC) cells were investigated and whether or not cotreatment with low doses of selenium would offer a therapeutic benefit was explored.


METHODS
Four CRC cell lines (Caco2, RKO, DLD1 and HT-29) with defined tumor signatures and seven different chemical forms of selenium were tested.


RESULTS
5-FU partially inhibited the HT-29 and RKO cells, but had a weak effect on the DLD1 and almost none on the Caco2 cells. Selenous acid and sodium selenite induced growth inhibition of the DLD1, RKO and HT-29 cells, with a marginal effect on the Caco2 cells. The Caco2 cells with mutant p53, failure to activate caspase-8, -9, -7 and -3 and with hypermethylated caspase-8 were resistant to 5-FU. Conversely, RKO cells expressing wildtype p53, proteolytically activated caspase-8, -9, -7 and -3 and unmethylated caspase-8 were more responsive to 5-FU and selenous acid-induced apoptosis.


CONCLUSIONS
Combination treatment with selenous acid may offer an efficacious strategy to overcome 5-FU resistance in certain CRC cells.
Thant
Aye Aye
AA
Division of Cancer Research and Training, Department of Medicine, Charles Drew University of Medicine and Science, Los Angeles, CA 90059, USA.
Wu
Yanyuan
Y
Lee
Jane
J
Mishra
Dhruva Kumar
DK
Garcia
Heather
H
Koeffler
H Phillip
HP
Vadgama
Jaydutt V
JV
D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D018938:Caco-2 Cells; D020169:Caspases / Q000378:metabolism*; D048708:Cell Growth Processes / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000494:pharmacology*; D019073:HT29 Cells; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008745:Methylation; D016566:Organoselenium Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D018036:Selenium Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D007527:Isoenzymes; D016566:Organoselenium Compounds; D018036:Selenium Compounds; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D020169:Caspases; D005472:Fluorouracil