Natural Products as Anticancer Agents: Current Status and Future Perspectives

Abstract

Natural products have been an invaluable and useful source of anticancer agents over the years. Several compounds have been synthesized from natural products by modifying their structures or by using naturally occurring compounds as building blocks in the synthesis of these compounds for various purposes in different fields, such as biology, medicine, and engineering. Multiple modern and costly treatments have been applied to combat cancer and limit its lethality, but the results are not significantly refreshing. Natural products, which are a significant source of new therapeutic drugs, are currently being investigated as potential cytotoxic agents and have shown a positive trend in preclinical research and have prompted numerous innovative strategies in order to combat cancer and expedite the clinical research. Natural products are becoming increasingly important for drug discovery due to their high molecular diversity and novel biofunctionality. Furthermore, natural products can provide superior efficacy and safety due to their unique molecular properties. The objective of the current review is to provide an overview of the emergence of natural products for the treatment and prevention of cancer, such as chemosensitizers, immunotherapeutics, combinatorial therapies with other anticancer drugs, novel formulations of natural products, and the molecular mechanisms underlying their anticancer properties.

Keywords: anti-cancer plants; bioactive anti-tumor agents; chemoprevention; chemotherapy; natural products; phytochemicals.

Figure 1

Curcumin inhibits cancer progression by regulating many signal pathways. (I) Akt/PI3K/mTOR signaling pathway. PTEN inhibits Akt activation by PI3K, mTOR phosphorylates p70S6K1 (S6K1), and 4E-BP1 which activate cell growth and survival pathways. Curcumin inhibits the Akt/PI3K/mTOR pathway by increasing PTEN expression through decreased miR-21 levels, and by inhibiting PI3K activity by upregulating miR-192-5p, miR-206, and miR-203; (II) MAPK signaling pathway. Signal cascades lead to activation of the MEKs, which subsequently activate the ERK1/2, p38, and JNK cascades and initiate the transcription of genes. Curcumin activates the p38 MAPK pathway by upregulating miR-378, which increases p21/27, cleaves caspase-3,9, and decreases Bcl-2 and MMP2/9. (III) Wnt/β-catenin pathway. The wnt molecule binds to both Frizzled and LRP5/6 receptors to cause the Axin/APC/GSK3β complex to dissociate. As a result, β-catenin is phosphorylated and translocated to the nucleus where it binds TCF/LEF co-transcription factors, which stimulate the transcription of Wnt-response genes. Curcumin inhibits Wnt/ β -catenin signaling through inhibition of lncRNA H19, lincROR, miR-130, 21, and upregulation of miR-192-5p and miR-33b; and (IV) JAK/STAT signaling. This pathway is activated when a ligand binds to a receptor, which communicates signals downstream STATs, whereas STATs are transcription factors that regulate gene expression; (V) p53 signaling pathway. The activation of MDM2 by AKT may inhibit the antitumor activity of p53. Curcumin inhibits lncRNA H19, miR-1246, and miR-19 to increase p53’s anti-tumor activity; (VI) NF-kB signaling pathway. This signaling cascade results in the phosphorylation of IkBα, which is then degraded by the proteasome. This allows the NF-kB/p65/p50 complex to translocate to the nucleus in order to facilitate transcription. This figure was reproduced from [32] (licensed under creative commons license).

Figure 2

The mechanism of chemoresistance in cancer cells may include a variety of molecular mechanisms, such as regulating drug influx and efflux through ABC transporters, inhibiting cell death, altering drug targets, regulating epigenetic factors, inactivating chemotherapeutic agents, inactivating tumor suppressor genes, modifying DNA repair processes, and modulating growth factor signaling (adapted from [33], License Number: 5433490420433, License date: 21 November 2022).

Figure 3

Several aspects of the development of cancer and the potential role of natural products in cancer prevention and therapy (adapted from [46], licensed under creative common attribution license).

Figure 4

Approved marketed anticancer drugs from 1950 to 2014 which are directly obtained or derived from natural products or imitate them (adopted from [428], licensed under creative common attribution license).