Exploring the recent trends in perturbing the cellular signaling pathways in cancer by natural products

Abstract

Cancer is commonly thought to be the product of irregular cell division. According to the World Health Organization (WHO), cancer is the major cause of death globally. Nature offers an abundant supply of bioactive compounds with high therapeutic efficacy. Anticancer effects have been studied in a variety of phytochemicals found in nature. When Food and Drug Administration (FDA)-approved anticancer drugs are combined with natural compounds, the effectiveness improves. Several agents have already progressed to clinical trials based on these promising results of natural compounds against various cancer forms. Natural compounds prevent cancer cell proliferation, development, and metastasis by inducing cell cycle arrest, activating intrinsic and extrinsic apoptosis pathways, generating reactive oxygen species (ROS), and down-regulating activated signaling pathways. These natural chemicals are known to affect numerous important cellular signaling pathways, such as NF-B, MAPK, Wnt, Notch, Akt, p53, AR, ER, and many others, to cause cell death signals and induce apoptosis in pre-cancerous or cancer cells without harming normal cells. As a result, non-toxic "natural drugs" taken from nature's bounty could be effective for the prevention of tumor progression and/or therapy of human malignancies, either alone or in combination with conventional treatments. Natural compounds have also been shown in preclinical studies to improve the sensitivity of resistant cancers to currently available chemotherapy agents. To summarize, preclinical and clinical findings against cancer indicate that natural-sourced compounds have promising anticancer efficacy. The vital purpose of these studies is to target cellular signaling pathways in cancer by natural compounds.

Keywords: cancer; metastasis; natural compounds; reactive oxygen species; therapeutic efficacy.

FIGURE 1

Aspects of herbal substances that contribute to their chemotherapeutic action (Laskar et al., 2020).

FIGURE 2

Notch signaling pathway. The ligand on the receiving cell connects the cell that acts as a presenter for the notch receptor. ADAM metalloprotease and γ-secretase split the Notch extracellular truncated (NEXT) domain, forming the notch intracellular domain (NICD). NICD is introduced into the nucleus and is a complex of transcription factors CSL 9 CBF1/hairless/lack 1 and transcriptional coactivator of mastermind-like proteins (MAML). The complex would then activate the target gene’s transcription. Treatment with diallyl trisulfide (DATS) boosts the expression of tumor suppressor microRNAs miR-143 and miR-145. When microRNAs bind to Notch1 mRNA, the mRNA is degraded, but the Notch1 protein is not translated. Curcumin inhibits Notch1 transcription and expression and the nucleus’ Hes-1, Hey-1, and Hey-2 genes (Angulo et al., 2017).

FIGURE 3

Hedgehog signaling and its interference in natural compounds. Upon binding of Hedgehog ligand (Hh) to Patched receptor, Smo is activated (Pathched generally inactivates Smo when it is not engaged with ligand). Then Smo brings about the translocation of Gli protein into the nucleus, subsequently causes the transcription of downstream genes. Compounds such as cyclopamine and genistein decrease the expression of Smo. Whereas nitidine chloride downregulates the expression of both Smo and Patched receptors. On the other hand, sulforaphane, nitidine chloride and genistein decrease the expression of Gli protein. Sulforaphane also reduces the expression of Smo, Gli and inhibits the nuclear translocation of Gli. Smo: Smoothened; Cos 2: Costal-2; SUFU: Suppressor of fused homolog; Hh: Hedgehog ligand (Skoda et al., 2018; Das et al., 2019).

FIGURE 4

PI3K/Akt/mTOR and Ras/Raf/MEK/ERK signaling pathways (Asati et al., 2016).

FIGURE 5

Effects of quercetin on lymphoma cells: proposed model. By inhibiting antiapoptotic signaling molecules and inducing proapoptotic proteins, which activate mitochondrial-mediated caspase activation and apoptosis, quercetin reduces cell proliferation (GULATI et al., 2006; Srivastava et al., 2016).