Apoptosis induced by aspirin and 5-fluorouracil in human colonic adenocarcinoma cells.
Various biochemical, clinical and epidemiological studies have shown that aspirin (ASA) and other nonsteroidal anti-inflammatory drugs (NSAIDs) demonstrate antineoplastic properties, particularly in the gastrointestinal tract, inhibiting the proliferation of colorectal cancer cells. The mechanism of action may be prostaglandin mediated through inhibition of the COX enzymatic system. This includes two iso-enzymes, COX-I and COX-II, working in concert with the activation of apoptosis, activation of immune surveillance, inhibition of proliferation, and inhibition of carcinogen activation. 5-Fluorouracil (5-FU) has demonstrated activity against colorectal cancer, leading to apoptosis of neoplastic cells. We evaluated the effects of varying doses of ASA (0.5, 1, 1.5 mM), both as a single agent and in combination with 5-FU (50 microg) in HT-29, a colon adenocarcinoma cell line. Proliferation assays showed that aspirin at a concentration of 1 mM inhibits cell growth. Cells treated with ASA, both alone and in combination with 5-FU, demonstrated apoptotic activity with the up-regulation of Bax protein, which is consistent with 5-FU anticancer treatment. Furthermore, there was synergistic cell death with ASA and 5-FU. DNA fragmentation, TUNEL, and trypan blue exclusion methods indicated that a combination of ASA and 5-FU induces apoptosis in cells in a time- and concentration-dependent manner. This study serves to further elucidate the mechanism of action of ASA, and ASA in combination with 5-FU, in colorectal cancer as evidenced by its effect on the HT-29 cell line.
Department of Medicine, Division of Hematology/Oncology, Howard University Cancer Center, Howard University, Washington, DC 20059, USA. hashktorab@howard.edu
Hassan
H
Ashktorab
Fitzroy W
FW
Dawkins
Rihab
R
Mohamed
Daniel
D
Larbi
Duane T
DT
Smoot
D000230:Adenocarcinoma / Q000188:drug therapy*; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D001241:Aspirin / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005472:Fluorouracil / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects; D051028:bcl-2-Associated X Protein
D000970:Antineoplastic Agents; C494826:BAX protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D001241:Aspirin; D005472:Fluorouracil