Use of Natural Products for Cancer Treatment

Published: 2021-09-13 15:40:11
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Cancer treatment typically involves surgery, radiotherapy and chemotherapy. More recently, hormonal therapy and target therapy are gained interestingly attention.
In breast cancer, chemotherapy is the main approach for treatment, mainly in metastatic tumors and typically involves a combination of different drugs or a drug that affect diverse targets. Not surprisingly, these approaches exhibit numerous side effects in patients. It can induce cell toxicity, liver and kidney damages, neurotoxicity, bone marrow suppression and can induce multidrug resistance witch lead to treatment failure. Besides that, the synthetic drugs used in chemotherapy can affect not only the cancer cells but also the non-tumor cells, inducing genotoxic, carcinogenic and teratogenic effects.On this point, natural products have been gained importantly attention on the field of cancer treatment and prevention due to their safety, low toxicity and availability. Natural products have been used to treat several diseases for decades and more recently, several studies have revealed interesting anti-carcinogenic properties for the development of new effective antitumor drugs. In the last years, several amount of anti-cancer drugs in the clinical are mainly phytochemicals obtained from teas, spices, and medicinal plants, or their analogues. In this regard there is a continuous need to search new powerful natural antitumor agents with low cytotoxic side-effects and can, in fact, inhibit tumor cell proliferation pathways without affecting the non-tumor cells.
The genus Eucalyptus belongs to the Myrtaceae family and are native from Australia. Nowadays different species of Eucalyptus are distributed around the world and are largely cultivated to produce paper, cellulose, timber, charcoal and pharmaceuticals, corresponding to one-third of the total forested area in Portugal. Regarding the medicinal uses, traditionally, Eucalyptus are used to produce essential oils for either cosmetics and pharmaceuticals. Besides that, it is used for herbal preparations to treat colds, pain, influenza, chest problems, fever and inflammation.
The genus Eucalyptus is an abundant source of phytochemicals and preliminary studies have been shown that some extracts and components of Eucalyptus possess cytotoxic and antiproliferative effects in different tumor cells. Eucalyptus contains high levels of volatile organic compounds being the monoterpene 1,8-cineole, known as eucalyptol, the major component found, which was associated with anticancer effects. Regarding the nonvolatile compounds, such as resveratrol, piceatannol, and macrocapal G, they also have shown to have growth inhibitory activity against different tumor cell lines. However, it is important to note that the cytotoxic activity is different depending on the part of the plant were the extract was sourced, the extraction method and the extracting solvent used. Besides that, the plant species, location, extraction conditions and sample preparation method influence the extraction efficiency of bioactive compounds.
Melissa Officinalis
Melissa Officinalis (lemon balm) is a member of the Lamiaceae family, originally native of Eastern Mediterranean region and Western Asia being now the most used medicinal plants in Europe and Mediterranean region. In Portugal, Melissa Officinalis is known as “erva-cidreira” and is commonly used as an herbal tea due its aromatic, digestive, sedative and antispasmodic properties. M. Officinalis possesses antibacterial, antifungal and anti-inflammatory effects and can be also used as an expectorant, headaches and rheumatism. Recently, some studies have reported its antioxidant, antiproliferative and antitumor effects. The main components of M. Officinalis are polyphenolic compounds, including essential oil (i.e. citronellal), caffeic acid derivatives (i.e. rosmarine acid, which correspond to the most abundant phenolic compound), flavonoids and quinic acid, fructose, glucose and γ-tocopherol.
Curcumin (1,7-bis(4-hydroxy- 3-methoxyphenyl)-1,6-heptadiene-3,5-dione) is a hydrophobic polyphenol present in the rhizome of Turmeric (Curcuma longa). Traditionally, Turmeric has been used in food flavoring, fabric coloring and medicinal applications particularly as an anti-inflammatory agent. Between the innumerous bioactive compounds isolated from Turmeric, Curcumin has been found as the compound with the greatest bioactivity. Curcumin possesses anti-inflammatory, antioxidant, antibacterial and anti-amyloid properties. Besides that, there are strong evidence that curcumin can be a potential anticancer agent. It has protective and therapeutic efficacy towards a board range of tumors such as breast, lung, pancreas, colorectal, skin and others.
Biological effects
Curcumin can, directly or indirectly, interact with several molecules through covalent or non-covalent hydrophobic bonding or hydrogen bonding. These molecular targets include enzymes, tumor suppressors, oncoproteins, transcription factors, inflammatory mediators and carrier proteins. It inhibits some cellular processes involved in carcinogenesis and tumor growth, suppress tumor angiogenesis and metastasis, acts on protein kinases (MAPK, Akt and Bcl-2), enzymes (COX-2, matrix metalloproteinases and LOX) and transcription factors (NF-κB, AP-1 and STAT-3). (ref. in “plano”) In addition, CUR can modulate different steps of molecular carcinogenesis. It has growth inhibition effect in several cancer cells without affecting normal cells; Modulate the cell proliferation and regulate cell cycle
Strategies to enhance curcumin bioavailability
Curcumin is a great promise in the prevention and treatment of cancer. Nevertheless, it has poor bioavailability related with its low water solubility, low serum levels, rapid metabolism, short half-life and limited tissue distribution. These characteristics constitute important barriers that limit its clinical efficacy. In order to improve CUR bioavailability, several approaches have been adopted including curcumin nanoparticles, liposomal and phospholipid complexes, polymer micelles and CUR structural modifications.
Curcumin nanoparticles
Nanoparticles (NPs) are solid and spherical structures ranging around 10-200 nm in size diameter. NPs are useful to improve the circulation of the loaded therapeutic molecules like hydrophilic and hydrophobic small drugs or biological macromolecules. Besides that, NPs also allows direct the drug to particular organs and controlled drug delivery. In terms of clinical uses, NPs must fulfill some characteristics such as biocompatibility, proper biodegradation kinetics and drug compatibility. Among the different types of NPs, polymer nanoparticles are the most attractive for drug delivery, in particular, particles prepared from polyesters like poly(lactide-co-glycolic acid) (PLGA), one of the most effective biodegradable polymeric NPs approved by the US FDA for drug delivery.
PLGA is a copolymer of poly lactic acid (PLA) and poly glycolic acid (PGA) and is considered a prevalent choice in several biomedical devices production due to its biodegradability and biocompatibility. In the body, PLGA undergoes hydrolysis to produce biodegradable metabolite monomers which are simply metabolized through the Krebs cycle. It is removed as carbon dioxide and water, thus the systemic toxicity is minimal. This type of NPs carries negative surface charge that promotes particle’s stability in circulation.
There are different methods for the preparation of PLGA NPs. For the encapsulation of hydrophobic molecules (i.e. curcumin), the common method used is the nanoprecipitation technique. In this case, the polymer and drug are dissolved in a polar solvent. This solution is dropwise added into an aqueous solution with surfactant which allows the rapid formation of the NPs by solvent diffusion. When formulating the NPs, is important to consider some parameters: the size, the surface charge, the drug release and the encapsulation efficiency. The size should be smaller than 200 nm in order to reach the cancer cells and to penetrate them.

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