Nonselective cyclooxygenase (COX) inhibition with ibuprofen attenuates tumor growth and liver metastasis and enhances the anti-tumor efficacy of chemotherapy in colorectal cancer (CRC)

1987

To examine whether the nonselective, inexpensive NSAID ibuprofen (IB) might likewise possess inhibitory effects on tumor growth and liver metastasis in established CRC, a series of mouse and human CRC cells and animal models were utilized. IB significantly inhibited in vitro cell proliferation in mouse (MC-26) and human (HT-29) CRC cell lines. In a syngeneic mouse subcutaneous CRC model, the administration of chow containing IB 1360 ppm, which achieved an average plasma concentration of IB below the peak level achieved in humans at therapeutic doses, inhibited tumor growth by 82.4% of control after 21 days of treatment. IB also prevented body weight loss in mice bearing MC-26 CRC cells (23.9 ± 2.6 g in ibuprofen vs. 20.3 ± 1.36 g in control). Fewer liver metastatic nodules were found in the IB group compared to the control group. Combination therapy was initiated 7 days after tumor injection into the splenic subcapsule by administering IB alone or IB with the standard antineoplastic agents, 5-fluoruracil (5-FU) or irinotecan (CPT-11), and continued for 21 days. Tumor volumes in the groups with IB ± CPT-11 or 5-FU were smaller than in the control group on day 14, 21, and 28. However, mice in the control group and the groups given 5-FU alone or 5-FU combined with ibuprofen ± CPT-11 had significant body weight loss compared with the groups not administered 5-FU. Moreover, some of the mice in those groups treated with 5-FU died even earlier than control mice. On day 50, the overall mortality was 100% in the control group, 20% in the IB group, 20% in the CPT-11 group, 10% in the IB/CPT-11 group, and 70% in the groups treated with 5-FU alone, 5-FU/CPT-11, IB/5-FU and IB/5-FU/CPT-11. No GI toxicity was detected in any of the mice treated with IB. In vitro angiogenesis assays indicated that IB decreased both cell proliferation and tube formation in human umbilical vein endothelial cells (HUVECs) and induced cell apoptosis after 24 h. Immunohistochemistry with CD 31 staining showed a decreased number of microvessels in IB-treated tumors compared to the control group. These studies demonstrate that IB, in part by modulating tumor angiogenesis, decreases both the growth and liver metastatic potential of CRC in mice, using IB doses that achieve blood levels in the range of therapeutic human plasma concentrations. Furthermore, IB potentiates the anti-tumor properties of CPT-11 and 5-FU in CRC. Finally, using this experimental model, IB improves the survival of mice treated with CPT-11, but not 5-FU.