Unraveling cancer progression pathways and phytochemical therapeutic strategies for its management

Abstract

Cancer prevention is currently envisioned as a molecular-based approach to prevent carcinogenesis in pre-cancerous stages, i.e., dysplasia and carcinoma in situ. Cancer is the second-leading cause of mortality worldwide, and a more than 61% increase is expected by 2040. A detailed exploration of cancer progression pathways, including the NF-kβ signaling pathway, Wnt-B catenin signaling pathway, JAK-STAT pathway, TNF-α-mediated pathway, MAPK/mTOR pathway, and apoptotic and angiogenic pathways and effector molecules involved in cancer development, has been discussed in the manuscript. Critical evaluation of these effector molecules through molecular approaches using phytomolecules can intersect cancer formation and its metastasis. Manipulation of effector molecules like NF-kβ, SOCS, β-catenin, BAX, BAK, VEGF, STAT, Bcl2, p53, caspases, and CDKs has played an important role in inhibiting tumor growth and its spread. Plant-derived secondary metabolites obtained from natural sources have been extensively studied for their cancer-preventing potential in the last few decades. Eugenol, anethole, capsaicin, sanguinarine, EGCG, 6-gingerol, and resveratrol are some examples of such interesting lead molecules and are mentioned in the manuscript. This work is an attempt to put forward a comprehensive approach to understanding cancer progression pathways and their management using effector herbal molecules. The role of different plant metabolites and their chronic toxicity profiling in modulating cancer development pathways has also been highlighted.

Keywords: cancer prevention; effector molecules; herbal metabolites; molecular pathways; toxicology.

FIGURE 1

Global cancer data. (A) Number of cancer cases in 2020 and the cases projected by 2040, as per WHO. (B) Number of deaths due to cancer reported until 2020 and the number of deaths projected up to the year 2040. (C) Number of cancer cases reported in the United States in 2023. (D) Cancer mortality data from 1930 to 2020. (E) Number of cancer-related deaths in different continents in a calendar year (2020).

FIGURE 2

Schematic representation of hallmarks of oncogenesis.

FIGURE 3

JAK/STAT in gene expression and cancer pathway. The interaction of cytokines or growth factors with their receptors (cytoplasmic tails of membrane cytokine receptors) induces dimerization/oligomerization of these receptors by inducing a conformational change in the cytoplasmic domain. JAKs or other families of tyrosine kinases are auto-phosphorylated or trans-phosphorylated as a result of this interaction. The phosphorylated JAKs form the sites for the binding of other signaling molecules with an SH2 domain (like STAT proteins) by phosphorylating the cytoplasmic tails of the receptor on tyrosine residues. Cytoplasmic STATs bind to phosphorylated receptors. STATs can assemble into homodimers or heterodimers that can translocate to the nucleus and activate gene transcription.

FIGURE 4

Wnt β-catenin signaling pathway in gene expression and cancer development. When Wnts are attached to their LRP5/6 and frizzled protein receptors, the cytoplasmic protein DVL is activated, which results in the inhibition of GSK3 in the destruction complex. The target gene is then transcriptionally regulated as a result of stabilized catenin binding to the TCF/LEF transcription factors in the nucleus.

FIGURE 5

p53 signaling pathway. DNA damage and oncogene activation is only a few of the cellular stressors that activate the sensor proteins ATM and CHK2. Murine double-minute 2 (MDM2), which is a target of p53 and also controls p53 stability, creates a negative feedback loop. Activated p53 is involved in numerous pathways, including apoptosis pathways, cell proliferation, and DNA repair and cell cycle arrest.

FIGURE 6

Role of the TNF-α in the progression of cancer and programmed cell death.

FIGURE 7

Intrinsic and extrinsic pathways of apoptosis.

FIGURE 8

Amplification of metastasis through VEGF upregulation.

FIGURE 9

Impact of phyto-analogs in preventing cancer pathogenesis.