Targeting the Tumor Extracellular Matrix by the Natural Molecule 4-Methylumbelliferone: A Complementary and Alternative Cancer Therapeutic Strategy

VITALE, DAIANA L.; ICARDI, ANTONELLA; ROSALES, PAOLO; SPINELLI, FIORELLA M.; SEVIC, INA; ALANIZ, LAURA D.

Frontiers in Oncology

Frontiers

Año: 2021 vol. 11

In antineoplastic therapy, one of the challenges is to adjust the treatment to the needs ofeach patient and reduce the toxicity caused by conventional antitumor strategies. It hasbeen demonstrated that natural products with antitumoral properties are less toxic thanchemotherapy and radiotherapy. Also, using already developed drugs allows developingsubstantially less costly methods for the discovery of new treatments than traditional drugdevelopment. Candidate molecules proposed for drug repositioning include 4-methylumbelliferone (4-MU), an orally available dietetic product, derivative of coumarinand mainly found in the plant family Umbelliferae or Apiaceae. 4-MU specifically inhibits thesynthesis of glycosaminoglycan hyaluronan (HA), which is its main mechanism of action.This agent reduces the availability of HA substrates and inhibits the activity of different HAsynthases. However, an effect independent of HA synthesis has also been observed. 4-MU acts as an inhibitor of tumor growth in different types of cancer. Particularly, 4-MU actson the proliferation, migration and invasion abilities of tumor cells and inhibits theprogression of cancer stem cells and the development of drug resistance. In addition,the effect of 4-MU impacts not only on tumor cells, but also on other components of thetumor microenvironment. Specifically, 4-MU can potentially act on immune, fibroblast andendothelial cells, and pro-tumor processes such as angiogenesis. Most of these effectsare consistent with the altered functions of HA during tumor progression and can beinterrupted by the action of 4-MU. While the potential advantage of 4-MU as an adjunct incancer therapy could improve therapeutic efficacy and reduce toxicities of otherantitumoral agents, the greatest challenge is the lack of scientific evidence to supportits approval. Therefore, crucial human clinical studies have yet to be done to respond tothis need. Here, we discuss and review the possible applications of 4-MU as an adjunct in conventional antineoplastic therapies, to achieve greater therapeutic success. We alsodescribe the main proposed mechanisms of action that promote an increase in theefficacy of conventional antineoplastic strategies in different types of cancer and prospectsthat promote 4-MU repositioning and application in cancer therapy.