PROMISING THERAPEUTICS FOR CANCER TREATMENT
Cancer and malaria are major health problems in the world despite the many strategies and therapies available for their treatment. The most widely used strategy for the treatment of these diseases is the administration of therapeutic drugs, which suffer from several shortcomings. Some of the pharmacological limitations associated with these drugs are multidrug resistance, drug toxicity, poor biocompatibility and bioavailability, and poor water solubility. Preclinical studies currently underway have demonstrated that combination therapy is a powerful approach that can overcome some of the aforementioned limitations. Artemisinin and its derivatives have been reported to show potent efficacy as anticancer and antimalarial agents. This review reports hybrid compounds containing artemisinin scaffolds and their derivatives with promising therapeutic effects for the treatment of cancer and malaria.
Cancer is also a chronic disease, and its burden continues to grow globally, disrupting health systems, families, communities, etc. In 2018, 18 million new cases and 9.6 million cancer-related deaths were reported. An increase of 1.2 million cancer cases and 400,000 deaths between 2018 and 2020 was estimated using the GLOBACAN database in 2021. More than 5 to 10% of cancer cases would have been transmitted via inherited genes, while 90-95% of cancer cases are believed to be caused by a genetic mutation.
The anticancer agents currently in use suffer from drug resistance and low specificity, resulting in some unwanted side effects. Therefore, there is an urgent need to design and develop new effective anticancer agents.
In the process of discovering new therapeutic agents for the treatment of cancer and malaria, artemisinin has been discovered. Artemisinin (qinghaosu) is a compound extracted from a medicinal plant found in China known as artemisia annua. It has been used in China for over 100 years to treat fever and chills. Combining artemisinin with other bioactive agents is a powerful strategy to overcome the challenges faced by known anticancer and antimalarial drugs. Artemisinin is currently one of the first-line treatments for malaria and occupies an important place in the medicinal industry because it exhibits a wide range of biological activities, including antimalarial, antifungal, anticancer, anti-HIV, antibacterial, etc.
Mechanism of artemisinin in cancer
Although artemisinin and its derivatives are well known as antiplasmodial agents, they also demonstrate significant cytotoxic effects on many cancer cell lines, including cells of the lung, breast, stomach, liver, colon, leukemia, cervical, melanoma, osteosarcoma, in vitro. There are many proposed mechanisms of action of artemisinin and its derivatives on cancer cells, but they all depend on the ability of the molecule to inhibit cell growth or destroy cell cycle stages via proliferation pathways. . Some studies have revealed that the artemisinin endoperoxide bridge interacts with intracellular iron or heme groups resulting in the production of cytotoxic radicals with alkylating activity. An increase in intracellular iron concentration can lead to a 100-fold increase in artemisinin cytotoxicity if tumor cells are encapsulated with iron or iron-saturated holotransferrin. Tumor cells have an increased demand for iron, and their iron metabolism rate and transferrin receptor expression are higher than normal cells, making them more sensitive to artemisinin cytotoxicity.
Another mechanism of artemisinin is the inhibition of metastases. Weifeng et al. demonstrated that artemisinin prevents metastasis by increasing cell-to-cell attachment through enhanced expression of Cdc42 and increased efficiency of the E-cadherin protein. All the reported modes of action of artemisinin and its derivatives reveal their anticancer activities by pleiotropic effects, in particular the inhibition of the proliferation of cancer cells, the induction of apoptosis, the stimulation of the inhibition of cancer. cell cycle, inhibition of angiogenesis, mediation of signaling pathways associated with tumors, destruction of cancer metastases, and invasion and regulation of the tumor microenvironment. More importantly, artemisinin and its derivatives exhibit minor toxic effects on normal body cells and overcome the multidrug resistance commonly reported in most anticancer drugs.
In-vivo studies revealed superior anticancer efficacy with inhibition of tumor growth and the tumor shrunk after 18 days of treatment in mice without significant weight loss.
The search for new, cost-effective and therapeutic agents with improved efficacy for the treatment of cancer and malaria has resulted in reports of several hybrid compounds containing artemisinin scaffolds. Some of the hybrid compounds have shown significant antimalarial and anticancer activity in vitro and in vivo with the potential to overcome drug resistance with good selectivity and low toxic side effects. In some of the research reports, the length and nature of the links between the parent drugs played an important role in the biological results of the compounds. The combination of artemisinin and its derivatives with known pharmacophores is a promising strategy for the development of improved and effective drugs. Despite all the research reports that have revealed the efficacy of artemisinin and its derivatives, there is still an urgent need to fully understand the mode of action of these compounds. Ongoing development and research on hybrid compounds containing artemisinin and derivatives will result in potent anticancer and antimalarial agents.
Hybrid compounds based on artemisinin and derivatives: promising therapeutics for the treatment of cancer and malaria
Department of Chemistry, University of Fort Hare, Alice 5700, South Africa