Abstract
Cisplatin is one of the most potent chemotherapeutic agents for the treatment of colon cancer. Nevertheless, the unavoidability of the notable toxicity and the development of the acquired resistance severely restricted its clinical application. Aspirin and some other non-steroidal anti-inflammatory drugs have been used to prevent colon tumorigenesis as chemopreventive agents. Here, we explored the possibility of aspirin as an adjuvant drug to boost the anti-cancer effect of cisplatin for colon cancer. We found that aspirin significantly enhanced the cisplatin-mediated inhibitions of cell proliferation, migration and invasion and the induction of apoptosis in colon cancer cells. The combined treatment of aspirin and cisplatin suppressed the expression of the anti-apoptotic protein Bcl-2 and the EMT-related proteins, up-regulated the levels of the cleaved PARP and Bax, and blocked the PI3K/AKT and RAF-MEK-ERK signaling pathway. In addition, we demonstrated that the enhanced effect of aspirin on the cisplatin-induced inhibition of tumor cell growth was also mediated through the suppression of the binding activity of NF-κB to the COX-2 promoter. The combination of aspirin and cisplatin effectively attenuated the translocation of NF-κB p65/p50 from the cytoplasm to the nucleus, and abrogated the binding of NF-κB p65/p50 to the COX-2 promoter, thereby down-regulating COX-2 expression and PGE2 synthesis. Moreover, the in vivo study also verified the enhanced anti-tumor activity of such combined therapy in colon cancer by targeting the NF-κB/COX-2 signaling. Our results provided new insights into understanding the molecular mechanisms of aspirin in sensitizing cisplatin-mediated chemotherapeutic effect in colon cancer and indicated a great potential of this combined therapy for cancer treatment.
Highlights
Colorectal cancer is the third common cancer and the fourth frequent cause of cancer death globally, with a rough estimate of 1.2 million new cases and 600,000 deaths per year
We found that Aspirin combined with Cisplatin led to more significant cancer cell proliferation, migration and invasion inhibition and apoptosis induction in vitro accompanied by the simultaneous inactivation of the PI3K/AKT and RAFMEK-ERK signaling pathway
Given that cyclooxygenase-2 (COX-2) is a known downstream effector of Aspirin contributing to its antiinflammation and tumor-suppressing effects, and the aberrant activation of COX-2/Prostaglandin E2 (PGE2) signaling axis has a critical role in promoting colon carcinogenesis [31, 32], we evaluated whether the synergistic anti-tumor efficacy caused by the combinational usage of Aspirin and Cisplatin was realized by targeting COX2
Summary
Colorectal cancer is the third common cancer and the fourth frequent cause of cancer death globally, with a rough estimate of 1.2 million new cases and 600,000 deaths per year. The morbidity of colonic malignancy tends to increase with the age. Colon cancer is more common in developed countries, the colon risk was found to be increased rapidly in developing countries [1,2,3]. The surgical excision is effective for over 80% of colorectal carcinomas, 50% of patients subsequently relapse with metastasis. Continuous radiochemotherapy treatment www.aging-us.com was widely taken in clinic to eliminate residual tumor cells, prolong disease-free intervals and improve overall survival [4]. The gradually developed radiochemotherapeutic resistance and the inevitable toxicity to normal cells strictly limited their effects
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