Colorectal Cancer Therapeutic Approaches: From Classical Drugs to New Nanoparticles

Colorectal cancer (CRC) is the second most commonly diagnosed cancer and the third leading cause of cancer related death in the world. Epidemiological studies show that CRC incidence and mortality vary substantially across different regions of the world. CRC is a multifactorial disease process, in which may intervene familial and hereditary factors, as well as age, environmental causes, lifestyle-related risk factors, namely diet and inflammatory conditions of the digestive tract. Several genetic alterations have been associated to the process of colon carcinogenesis, namely epidermal growth factor receptor (EGFR) activation, BRAF and KRAS mutations among others.

Many options for CRC treatment are available, including surgery, chemotherapy, and radiation. Herein, we will describe the main classical drugs used in CRC chemotherapy, such as 5-Fluoracil, Leucovorin, Irinotecan, and Oxaliplatin. Recent anti-CRC therapies are now targeting specifically signaling pathways implicated in colorectal carcinogenesis, such as EGFR (Cetuximab, Matuzumab, Erlotinib, Panitumumab), which appears highly overexpressed in most CRC patient cases. However, this approach is limited by resistance conferred by the activation of mutations in EGFR downstream signaling pathways. As a result, an increasing number of specific components of these pathways have been targeted in order to overcome the resistance to conventional EGFR-targeted therapies. Despite the recent advances, conventional chemotherapy remains unable to improve the prognosis of advanced or recurrent CRC.

In colorectal environment, there is a symbiotic relationship between intestinal cells and bacteria from the diet. Indeed, colonocytes metabolize short-chain fatty acids (SCFA), byproducts of anaerobic bacterial fermentation of dietary fiber. These SCFAs play a significant role in maintaining the normal physiological functions of the colon mucosa, but they also have strong anti-tumorigenic properties, such as reduction of cancer cell proliferation and differentiation and stimulation of apoptosis in CRC cells. Here we discuss the exploitation of anti-apoptotic features of SCFA in the development of new prevention and therapeutic approaches.

Changes in cellular metabolism are a crucial hallmark of cancer and CRCs were shown to present a glycolytic phenotype even in the presence of oxygen, phenomenon commonly designated as the ‘Warburg effect’. We will also discuss the use of metabolic inhibitors as new therapeutic adjuvants per se or in combination with other therapies.

To reduce off-target associated adverse effects and achieve targeted drug delivery in cancer therapy, nanomedicine is emerging as a promising strategy. The transport of classical drugs by nanoparticles has shown great promise in improving drug distribution and bioavailability, increasing the anticancer molecules concentration at the cancer tissue, providing optimal drug delivery, and minimizing drug toxicity. Additionally, targeting CRC cells may be improved by incorporating ligands for cancer-specific surface receptors such as EGFR, bringing new opportunities in the treatment of patients with CRC.

Keywords: Bevacizumab, Cetuximab, Classical chemotherapy, Colorectal cancer, 5-Fluoracil, Irinotecan, Metabolic targets, Nanoparticles, Oxaliplatin, Panitumumab, Target therapy.