Abstract
In antineoplastic therapy, one of the challenges is to adjust the treatment to the needs of each patient and reduce the toxicity caused by conventional antitumor strategies. It has been demonstrated that natural products with antitumoral properties are less toxic than chemotherapy and radiotherapy. Also, using already developed drugs allows developing substantially less costly methods for the discovery of new treatments than traditional drug development. Candidate molecules proposed for drug repositioning include 4-methylumbelliferone (4-MU), an orally available dietetic product, derivative of coumarin and mainly found in the plant family Umbelliferae or Apiaceae. 4-MU specifically inhibits the synthesis 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 HA synthases. 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 acts on the proliferation, migration and invasion abilities of tumor cells and inhibits the progression 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 the tumor microenvironment. Specifically, 4-MU can potentially act on immune, fibroblast and endothelial cells, and pro-tumor processes such as angiogenesis. Most of these effects are consistent with the altered functions of HA during tumor progression and can be interrupted by the action of 4-MU. While the potential advantage of 4-MU as an adjunct in cancer therapy could improve therapeutic efficacy and reduce toxicities of other antitumoral agents, the greatest challenge is the lack of scientific evidence to support its approval. Therefore, crucial human clinical studies have yet to be done to respond to this 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 also describe the main proposed mechanisms of action that promote an increase in the efficacy of conventional antineoplastic strategies in different types of cancer and prospects that promote 4-MU repositioning and application in cancer therapy.
Highlights
Natural products derived from plants have been extensively used for thousands of years
It is likely that 4-MU can affect the synthesis and organization of other extracellular matrix (ECM) components, such as other noncellular components of the tumor microenvironment (TME)
In trabecular meshwork cells of the eye, Keller et al found that 4-MU reduced the ECM components versican and fibronectin, and that the addition of exogenous HA failed to reverse the effects of 4-MU [123]
Summary
Natural products derived from plants have been extensively used for thousands of years. It has been described that coumarin and its derivatives have diverse biological effects, acting as anti-inflammatory [4], anticoagulant [5], antiviral [6], fungicidal [7] and antitumor agents [8]. They are benzo-a-pyrones (IUPAC nomenclature: 2H-chromen-2-one), which consist of a benzene ring joined to a pyrone ring. Umbelliferones are widely distributed among the plant families Rutaceae, Umbelliferae (celery, anise) and Asteraceae (chamomile) [1] Since these compounds are not extracted from plants, they are synthesized using the “Pechmann” condensation reaction of resorcinol and formyl acetic acid [10]. In this review, we discuss the tumor process that might be modulated by 4-MU, focusing on the type of tumor as well as on its action on different tumor-associated cells besides the tumor cell itself
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