Non-steroidal anti-inflammatory drugs and biomarkers: A new paradigm in colorectal cancer

Abstract

Colorectal cancer is a sporadic, hereditary, or familial based disease in its origin, caused due to diverse set of mutations in large intestinal epithelial cells. Colorectal cancer (CRC) is a common and deadly disease that accounts for the 4^th worldwide highly variable malignancy. For the early detection of CRC, the most common predictive biomarker found endogenously are KRAS and ctDNA/cfDNA along with SEPT9 methylated DNA. Early detection and screening for CRC are necessary and multiple methods can be employed to screen and perform early diagnosis of CRC. Colonoscopy, an invasive method is most prevalent for diagnosing CRC or confirming the positive result as compared to other screening methods whereas several non-invasive techniques such as molecular analysis of breath, urine, blood, and stool can also be performed for early detection. Interestingly, widely used medicines known as non-steroidal anti-inflammatory drugs (NSAIDs) to reduce pain and inflammation have reported chemopreventive impact on gastrointestinal malignancies, especially CRC in several epidemiological and preclinical types of research. NSAID acts by inhibiting two cyclooxygenase enzymes, thereby preventing the synthesis of prostaglandins (PGs) and causing NSAID-induced apoptosis and growth inhibition in CRC cells. This review paper majorly focuses on the diversity of natural and synthetic biomarkers and various techniques for the early detection of CRC. An approach toward current advancement in CRC detection techniques and the role of NSAIDs in CRC chemoprevention has been explored systematically. Several prominent governing mechanisms of the anti-cancer effects of NSAIDs and their synergistic effect with statins for an effective chemopreventive measure have also been discussed in this review paper.

Keywords: COX-pathways; KRAS; NSAIDs; biomarkers; chemoprevention; colonoscopy; colorectal cancer; statins.

Figure 1

A detailed diagrammatic overview of Synthetic Biomarkers on the basis of their activity and various methodologies for endogenous administration.

Figure 2

Cox-dependent and independent mechanism overview associated with NSAIDs. Cyclooxygenase dependent and independent pathways play a significant role in anti-tumorigenesis. The major anticancer action of NSAIDs is thought to be COX 2 suppression mediated decrease of prostaglandin E2 synthesis, which inhibits tumor cell proliferation and angiogenesis while increasing apoptosis.

Figure 3

An overview of downstream targets in colorectal cancer & NF-κB and β-catenin/Wnt pathways. Catenin accumulates as a result of APC gene or activating mutations in the β-catenin, which leads to the formation of complex with the TCF/LEF transcription factors. TCF can interact with extra to stimulate the transcription of genes which are proliferative in the colon, including c-Myc and cyclinD1. With the release of p65, that is subsequently translocated to nucleus, inflammatory cytokines activate NF- κB, which leads to an increase in target gene transcription. NSAIDs in combination with other drugs like naproxen or sulindac targets β-catenin /Wnt and NF-κB pathways and suppresses downstream signaling.

Figure 4

Anticancer effects exerted by Statins by inhibiting mevalonate pathway. Acetyl-CoA, the byproduct of glycolysis, is converted into mevalonate, IPP, GPP, FPP, GGPP, and cholesterol through a series of enzymatic processes that make up the mevalonate pathway. FPP and GGPP may both be supplemented to proteins post-translationally, particularly minor monomeric GTPases such as Ras predominantly part of MAPK/ERK pathway responsible for inducing VEGF expression in colorectal cancer. The inhibitory effect of FPP on MAPK/ERK pathway and inhibition of mevalonate pathway by statins causes tumor cell death and prevents migration of tumor cells. Statins shows its inhibitory effect on VEGFR and EGFR thus, inhibiting angiogenesis and tumor progression in cancer. It also inhibits BCL2 and induces aoptosis of cancerous cells.

Figure 5

Synergistic action of statins and NSAIDs: Statins repress and activate signaling cascades that result in cell-cycle arrest, cell death, apoptosis, and autophagy when used with anti-cancer medications such TRAIL, troglitazone, celecoxib, gemcitabine, cisplatin.