Natural Products Attenuating Biosynthesis, Processing, and Activity of Ras Oncoproteins: State of the Art and Future Perspectives

Abstract

RAS genes encode signaling proteins, which, in mammalian cells, act as molecular switches regulating critical cellular processes as proliferation, growth, differentiation, survival, motility, and metabolism in response to specific stimuli. Deregulation of Ras functions has a high impact on human health: gain-of-function point mutations in RAS genes are found in some developmental disorders and thirty percent of all human cancers, including the deadliest. For this reason, the pathogenic Ras variants represent important clinical targets against which to develop novel, effective, and possibly selective pharmacological inhibitors. Natural products represent a virtually unlimited resource of structurally different compounds from which one could draw on for this purpose, given the improvements in isolation and screening of active molecules from complex sources. After a summary of Ras proteins molecular and regulatory features and Ras-dependent pathways relevant for drug development, we point out the most promising inhibitory approaches, the known druggable sites of wild-type and oncogenic Ras mutants, and describe the known natural compounds capable of attenuating Ras signaling. Finally, we highlight critical issues and perspectives for the future selection of potential Ras inhibitors from natural sources.

Erucin, a natural isothiocyanate, exerts pro‐angiogenic properties in cultured endothelial cells and reverts angiogenic impairment induced by high glucose

“…As previous reports show an interaction of natural compounds and Ras (Appari et al, 2014; Tisi et al, 2020), we investigated the ability of ERU to directly activate Ras. Ras activation was studied by immunoblotting of pulled down Ras‐RAF complets.…”

Quercetin, a Flavonoid with Great Pharmacological Capacity

“…According to several studies, quercetin can prevent Ras proteins from being expressed. In one study, quercetin was found to inhibit the expression of Harvey rat sarcoma (H-Ras), K-Ras, and neuroblastoma rat sarcoma (N-Ras) in human breast cancer cells, leading to decreased proliferation and increased apoptosis [ 109 ]. For instance, using several human cancer cell models, quercetin was shown to preferentially reduce the oncogenic Ras protein over wild-type Ras by a post-translational mechanism.…”

Targeting Autophagy with Natural Products as a Potential Therapeutic Approach for Cancer

“…Therefore, as shown in Figure 3 , the enhanced expression of LC3-II in the stromal cells of ovarian cancer may fuel the growth of cancer cells. Natural products have historically been regarded as different doctrines of traditional medicine or folk medicine for the management and treatment of a variety of human diseases, including cancer, by inhibiting autophagy pathways [ 4 , 44 , 45 ]. Several studies have shown that the inhibition of autophagy using natural compounds can effectively enhance the cancer cell death induced by diverse anticancer drugs.…”