Recent advance of herbal medicines in cancer- a molecular approach

Abstract

Bioactive compounds are crucial for an extensive range of therapeutic uses, and some exhibit anticancer activity. Scientists advocate that phytochemicals modulate autophagy and apoptosis, involved in the underlying pathobiology of cancer development and regulation. The pharmacological aiming of the autophagy-apoptosis signaling pathway using phytocompounds hence offers an auspicious method that is complementary to conventional cancer chemotherapy. The current review aims to explore the molecular level of the autophagic-apoptotic pathway to know its implication in the pathobiology of cancer and explore the essential cellular process as a druggable anticancer target and therapeutic emergence of naturally derived phytocompound-based anticancer agents. The data in the review were collected from scientific databases such as Google search, Web of Science, PubMed, Scopus, Medline, and Clinical Trials. With a broad outlook, we investigated their cutting-edge scientifically revealed and/or searched pharmacologic effects, a novel mechanism of action, and molecular signaling pathway of phytochemicals in cancer therapy. In this review, the evidence is focused on molecular pharmacology, specifically caspase, Nrf2, NF-kB, autophagic-apoptotic pathway, and several mechanisms to understand their role in cancer biology.

Keywords: Anticancer; Apoptosis; Autophagy; Molecular mechanism; Pharmacology; Phytochemicals.

Fig. 1

Herbal formulations, such as extracts or formulations, are being studied as supplement therapies for chemotherapy and/or radiotherapy against a variety of cancers. Reproduced with permission from Ref. [82] which was published under a CC BY license.

Fig. 2

The autophagic pathway's molecular mechanism. The development of a pre-autophagosomal structure initiates autophagy. The development of pre-autophagosomal structures is aided by PI3K-AMPK and mTOR. ULK1, Vps34, and the Beclin-1 complex all plays a role in phagophore formation. Autolysosomes are formed when mature autophagosomes bind to lysosomes. Finally, acid hydrolases remove autolysosomes by producing nutrients and recycling metabolites. Reproduced with permission from [03] which was published under a CC BY license.

Fig. 3

Apoptotic pathway mechanism in cancer. In this mechanism two central pathways i.e. the intrinsic and extrinsic pathways are involved to initiate apoptosis. The TNF-/TNFR1 and FasL/FasR models clearly explain the extrinsic pathway of apoptosis. An adaptor protein creates the death receptor in this case; adaptor proteins contain FADD and TRADD. The extrinsic pathway signaling causes the attachment of DRs to precise death ligands (DLs), resulting in a DISC. The complex caspase-8 activation pathway follows a pre-defined system that allows caspase-8 to separate from the DISC, regardless of whether the pro-domain of caspase-8 is kept as a part of the DISC to pledge the signaling stages of apoptosis. Nonetheless, in the majority of apoptotic cells, proteins such as caspase-9, SMAC/DIABLO, Bcl-2, Bcl-w, and MYC are usually involved in intrinsic stages. Mitochondrial deactivation is followed by loss of potential of the mitochondrial interior membrane, plenty of development of superoxide ions, decreased the development of mitochondrial biogenesis, discharge of intra-membranous proteins, and matrix calcium glutathione rupture, all of that summarize the significant potential for cancer treatment plans through activating the intrinsic phases of apoptosis in cancer cells. Caspases that initiate apoptosis, i.e. caspase-8-9, Poly (ADP-ribose polymerase (PARP), and other caspases, i.e. caspase-3-6, −7 and 10, are termed as assassin caspases (Fig. 3). Reproduced with permission from [03] which was published under a CC BY license.

Fig. 4

In cancer, major phytoconstituents produce signal transduction pathways that control autophagic and apoptotic cell death. Individually, phytoconstituents have been shown to stimulate the intrinsic and extrinsic apoptotic pathways by disrupting mitochondrial-caspase-9 and FAS-ligand-caspase-8 arbitrated apoptotic cell death. Phytoconstituents cause both ER stress as well as apoptotic cell death. Several phytoconstituents, however, influence mitochondrial biogenesis and confirm apoptosis-autophagic cell death. In cancer cells, phytoconstituents control the cell cycle and microRNA then causes apoptosis autophagic cell death. On the other hand, many phytochemicals stimulate autophagic signaling while inhibiting cell growth and autophagy. Reproduced with permission from [03] which was published under a CC BY license.

Fig. 5

Phytochemical mechanism of action of chemopreventive agents on NF-kB and AP1. Reproduced with permission from Ref. [201].

Fig. 6

Phytochemicals regulate Nrf2-mediated gene transcription. Keap1 protein keeps Nrf2 in the cytoplasm under homeostatic conditions. Chemopreventive phytoconstituents directly interact with Keap1 cysteine residues, causing Nrf2 to be released from the complex. Chemopreventive drug-produced ROS can stimulate an extensive range of kinase signaling pathways, comprising PI3K, PKC, and MAPK, and all can cause Nrf2 expression and translocation from the cytosol to the nucleus. Reproduced with permission from Ref. [206] which was published under a CC BY license.

Fig. 7

A summary of the PI3K/AKT/mTOR signaling pathway. Reproduced with permission from Ref. [214] which was published under a CC BY license.

Fig. 8

Angiogenesis of the tumour and the metastatic process. The proteins such as VEGF-A, MMPs, HIF-1A, chemokines, cytokines, and growth factors are among the proangiogenic and protumorigenic factors released by cancer cells. Endothelial cells (ECs) in tip cells, which direct emergent vessels, and stem cells, which are involved in vessel stability, are stimulated by VEGF-A. Furthermore, cancer cells secrete cytokines that stimulate cancer-related fibroblasts (CAFs) and stimulated tumour-related macrophages (TAMs), promoting cancer stem cell intravasation (CSCs). Cancer cells circulating in the bloodstream arrive in the target organ, appear, and begin to proliferate and spread. Reproduced with permission from Ref. [220] which was published under a CC BY license.

Fig. 9

Various phytochemicals are involved in regulating an extensive range of molecular processes in order to modulate skin cancer. Reproduced with permission from Ref. [222] which was published under a CC BY license.