Natural Alternatives in the Treatment of Colorectal Cancer: A Mechanisms Perspective

Abstract

Colorectal cancer (CRC) is one of the deadliest neoplasia. Intrinsic or acquired resistance is the main cause of failure of therapy regimens that leads to relapse and death in CRC patients. The widely used chemotherapeutic agent 5-fluorouracil (5-FU) remains the mainstay for therapeutic combinations. Unfortunately, chemotherapeutic resistance and side effects are frequent events that compromise the success of these therapies; the dysregulation of enzymes that regulate 5-FU metabolism increases the expression and activity of efflux pumps. Additional tumor cell adaptations such as epithelial-mesenchymal transition (EMT), autophagy shaping of the tumor microenvironment, and inflammation contribute to chemoresistance. Finding new strategies and alternatives to enhance conventional chemotherapies has become necessary. Recently, the study of natural compounds has been gaining strength as an alternative to chemotherapeutics in different cancers. Curcumin, trimethylglycine, resveratrol, artemisinin, and some helminth-derived molecules, among others, are some natural compounds studied in the context of CRC. This review discusses the main benefits, mechanisms, advances, and dark side of conventional chemotherapeutics currently evaluated in CRC treatment. We also analyzed the landscape of alternative non-conventional compounds and their underlying mechanisms of action, which could, in the short term, provide fundamental knowledge to harness their anti-tumor effects and allow them to be used as alternative adjuvant therapies.

Keywords: adjuvants; bioactive compounds; chemoresistance; chemosensitivity; colorectal cancer; natural compounds.

Figure 1

A flowchart of the methodological approach that was followed for the selection/exclusion of the articles.

Figure 2

Main mechanisms and alterations in tumors that lead to evasion of cell death and, consequently, chemoresistance and tumor relapse. Inflammation, increment of drug targets, alteration in functions of efflux pumps, acquisition of epithelial–mesenchymal transition (EMT) markers, autophagy, presence of cancer stem cells (CSCs), increment of anti-apoptotic proteins, and tumor microenvironment.

Figure 3

The 5-FU metabolism and inhibition of thymidylate synthase activity.

Figure 4

The main mechanisms of action related to the effect of curcumin in 5-Fluorouracil (5-FU) resistance colorectal cancer cells. Previous studies have verified the use of curcumin in 5-FU and its effects as regulator of cell cycle arrest, increasing P21 protein expression and the negative regulation of cyclin B1, cyclin-dependent kinases 1, 2, and 4 (CDK1, CDK2, CDK4), cyclin A2, and the phosphorylation of retinoblastoma, decreasing the expression of ABC transporters, regulating EMT markers such as E-cadherin positively, and reducing Vimentin and Slung proteins. Finally, curcumin has an important effect on regulating stemness markers such as CD116, CD44, ALDH1, CD33, and the polycomb repressive complex.

Figure 5

The mechanisms of action and metabolism of TMG. TMG is an osmolyte that functions mainly in the kidney, protecting renal cells from high urea levels and electrolytes. TMG acts as a methyl group donor, switching from trimethylglycine to dimethylglycine, which helps to convert homocysteine to methionine via betaine–homocysteine methyl transferase (BHMT).

Figure 6

The mechanisms and alterations in tumors that lead to chemoresistance and its potential regulation by natural compounds, such as trimethylglycine, curcumin, resveratrol, artemisinin, and, recently, helminth-derived molecules together with 5FU. The black dotted lines indicate the blocking effect of a natural compound, while the gray lines with arrowheads show the induction of the mechanism related to better responses to treatments.