No abstract

Natural products are enriched with numerous compounds with a broad spectrum of therapeutics indication suggesting the role of functional moieties as a core pharmacophore. This review highlights the role of triterpene in targeting signaling pathways in cancer. Advancement in cellular, biochemical, experimental, and computational approaches provides new insights into various pathways in cancer. In signaling network, triterpenes primarily target membrane receptors which control and modulates expression level of the biological responses. Triterpenes are immunomodulatory targeting nuclear factor kappa B, toll-like receptors, signal transducer and activator of transcription 3, and PI3K/Akt/mTOR. Triterpenes isolated from plants and fungus mainly focus on the process of apoptosis while other signaling areas in the cancer are still shrouded. Some of the triterpenes have already passed the clinical trial, whereas many more have been proven to yield effective results. This review would help the researchers to study the role of triterpenes in cancer, thus, helping them to discover and design efficacious therapeutics agents.

Lung cancer causes huge mortality to population, and pharmaceutical companies require new drugs as an alternative either synthetic or natural targeting lung cancer. The conventional therapies cause side effects, and therefore, natural products are used as a therapeutic candidate in lung cancer. Chemical diversity among natural products highlights the impact of evolution and survival of fittest. One such neglected natural product is Ganoderma lucidum used for promoting health and longevity for a longer time. The major bioconstituents of G. lucidum are mainly terpenes, polysaccharides, and proteins, which were explored for various activities ranging from apoptosis to autophagy. The bioconstituents of G. lucidum activate plasma membrane receptors and initiate various downstream signaling leading to nuclear factor-κB, phosphoinositide 3-kinase, Akt, and mammalian target of rapamycin in cancer. The bioconstituents regulate the expression of various genes involved in cell cycle, immune response, apoptosis, and autophagy in lung cancer. This review highlights the inextricable role of G. lucidum and its bioconstituents in lung cancer signaling for the first time.

Wnt signaling pathways are the group of signaling transduction controlling the embryonic development, cell proliferation, cell migration, cell fate specification, and body axis pattern. Nuclear accumulation of β-catenin in Wnt signaling is a widely recognized marker of poor cancer prognosis which regulates fat and glucose metabolism. Ganoderic acid is a triterpene isolated from fungus Ganoderma lucidum renowned for its pharmacological effects. The present study revealed the mechanistic study of β-catenin with 50 isoforms of ganoderic acid by molecular docking using Maestro 9.6 (Schrödinger Inc) in Wnt signaling pathway. Molecular docking reveals the binding interaction of β-catenin and ganoderic acid A with GScore (-9.44), kcal/mol, lipophilic EvdW (-2.86), electro (-0.72), Glide emodel (-50.401), MM-GBSA (-87.441), H bond (-1.91) with Lys 180 and Asn 220 residues involved in hydrogen bonding. Qikprop analyzed the absorption, distribution, metabolism, excretion, and toxicity and confirmed that most of the isoforms satisfies Lipinski rule but needs little modifications in their structure. The ganoderic acid A is the best-docked isoforms which inhibits the proliferation, viability, and intracellular ROS of pancreatic cancer RIN-5F cells in a dose-dependent manner.

Receptor tyrosine kinases (RTKs) are transmembrane high-affinity surface receptors responsible for cell migration, adhesion, apoptosis, metabolism, and cell proliferation activities in various cancers. Minute aberration in the RTK signaling modulates the downstream signaling pathways that results in cancer. Ganoderic acid is a triterpene isolated from Ganoderma lucidum, which is renowned for its therapeutics effect, especially in cancer. The present study discusses receptor-based molecular docking of insulin receptor (IR), insulin-like growth factor receptor 1 (IGFR-1), vascular endothelial growth factor receptor-1 (VEGFR-1), vascular endothelial growth factor receptor-2 (VEGFR-2), and estrogen receptor (ER) with 50 isoforms of ganoderic acid along with natural inhibitors. These receptors were assessed for toxicity (ADMET) by using Maestro 9.6 (Schrödinger Inc). The calculated docking free energy yielded an excellent dock score for the ganoderic acid when docked with proteins IR, IGFR-1, VEGFR-1, VEGFR-2, and ER, suggesting its potential in combating cancer. Protein-ligand profile highlighted the binding interactions comprising lipophilic, hydrogen bonding, pi-pi stacking interactions, and noncovalent bonding which play a pivotal role in targeting cancer. In silico studies revealed structure of ganoderic acid A as best isoforms among 50 isoforms which exhibits biological activity in liver cancer cells. Ganoderic acids A significantly decrease the viability, proliferation, and oxidative stress in a dose-dependent manner in liver cancer cells.

A Basidiomycetes fungus belonging to polypore family of mushrooms, Ganoderma lucidum (GL), has been known since a long time for their myriad therapeutic indications. Renowned as an invaluable resource of cardinal mycoconstituents they encompass numerous terpenoids polysaccharides and proteins. Possessing the therapeutically potent lanosteroidal skeleton, terpenoids are upheld for their invariable participation in therapeutically diverse bioactivities. Polysaccharides and proteins exhibiting distinguishable bioactivities provide this oriental mushroom with additional edges over immune function and anti-cancer potential. This review is a concerted effort to throw light upon the therapeutic versatility of the fungus, shadowed by various other natural products. An effort has been made towards conglomerating the mycoconstituents decisive for the many activities portrayed by this fungus. More importantly, this review seeks to fathom the inextricable role played by derivatives in modulating signaling cascades such as downregulation of various mitogenic pathways, inhibiting growth factors, or upregulating certain pathways enhancing cellular integrity.

Cancer is a multifactorial disease, causing behavioral and metabolic alterations, leading to uncontrolled cell proliferation with collateral weakening of immune system. Crucial balance between cell proliferation and cell death determines the fate of a cell, which might progress towards survival or apoptosis. Apoptosis is a complex, programmed, and highly regulated process causing dramatic morphological and biochemical perturbations in the cellular machinery. Ganoderma lucidum is a basidiomycetes, polypore mushroom known for its pharmacological properties in cancer. The major bioconstituents in G. lucidum are terpenoids, polysaccharides, and proteins that target cancer-signaling factors like plasma membrane receptors proteins and adapter molecules. Of all constituents, the major terpenoid, i.e. Ganoderic acid is reported to interact with membrane receptors mainly, receptor tyrosine kinase (RTKs). Ganoderic acid interacts and modulates the signaling network in IR, IGFR-1, IGFR-2, VEGFR-1, VEFGR-2, and EGFR in cancer signaling pathways. It primarily targets NF-κB, RAS-MAPK, PI3K/Akt/mTOR, and cell cycle resulting in apoptosis. This review highlights the role of ganoderic acid in apoptosis and modulations of various signaling proteins in cancer.

Evaluating anti-oxidant potential of Ganoderic acid A in STAT 3 pathway in Prostate cancer. Molecular docking and ADMET activities of different isoforms of ganoderic acid on STAT 3 pathway were performed by Maestro 9.6 (Schrödinger Inc). The ganoderic acid A is best-docked among isoforms which analyses the expression level of antioxidant and STAT 3 pathway in PC-3 cells. The receptor-based molecular docking reveals the best binding interaction of SH2 domain of STAT3 and ganoderic acid A with GScore (-6.134), kcal/mol, Lipophilic EvdW (-1.83), Electro (-1.1), Glide emodel (-31.857), H bond (1.98), MM-GBSA (-69.555). The molecular docking QikProp analyzed the absorption, distribution, metabolism, excretion, and toxicity (ADME/T). The ganoderic acid A is best-docked among isoforms which downregulates the expression of STAT 3 in PC-3 cells. Moreover, ganoderic acid A inhibits proliferation, viability, ROS, DPPH, and analyzed the expression of SOD1, SOD2, and SOD3 by Real time PCR in a PC-3 cell in a dose-dependent manner. Molecular docking revealed the mechanistic binding of Ganoderic acid A in STAT3 signaling, which inhibits the proliferation, viability, and ROS in PC-3 cells.