Multifunctional Roles of Betulinic Acid in Cancer Chemoprevention: Spotlight on JAK/STAT, VEGF, EGF/EGFR, TRAIL/TRAIL-R, AKT/mTOR and Non-Coding RNAs in the Inhibition of Carcinogenesis and Metastasis

Abstract

The pursual of novel anticancer molecules from natural sources has gained worthwhile appreciation, and a significant fraction of conceptual knowledge has revolutionized our understanding about heterogeneous nature of cancer. Betulinic acid has fascinated interdisciplinary researchers due to its tremendous pharmacological properties. Ground-breaking discoveries have unraveled previously unprecedented empirical proof-of-concept about momentous chemopreventive role of betulinic acid against carcinogenesis and metastasis. Deregulation of cell signaling pathways has been reported to play a linchpin role in cancer progression and colonization of metastatically competent cancer cells to the distant organs for the development of secondary tumors. Importantly, betulinic acid has demonstrated unique properties to mechanistically modulate oncogenic transduction cascades. In this mini-review, we have attempted to provide a sophisticated compendium of regulatory role of betulinic acid in cancer chemoprevention. We have partitioned this multi-component review into different sections in which we summarized landmark research-works which highlighted betulinic acid mediated regulation of JAK/STAT, VEGF, EGF/EGFR, TRAIL/TRAIL-R, AKT/mTOR and ubiquitination pathways in the inhibition of cancer. In parallel, betulinic acid mediated regulation of signaling cascades and non-coding RNAs will be critically analyzed in cell culture and animal model studies. Better comprehension of the pharmaceutical features of betulinic acid and mapping of the existing knowledge gaps will be valuable in the translatability of preclinical studies into rationally designed clinical trials.

Pentacyclic Triterpenoid Phytochemicals with Anticancer Activity: Updated Studies on Mechanisms and Targeted Delivery

“…Effects on JAK/STAT, VEGF, EGF/EGFR, TRAIL/TRAIL-R, and AKT/mTOR [67] Water-soluble composites of B dipropionate tested in vitro against ascites carcinoma cells and human lung adenocarcinoma cells…”

Identifying potential risk genes for clear cell renal cell carcinoma with deep reinforcement learning

“…EGFR was notably upregulated in ccRCC tumor tissues compared to normal tissues. EGFR is activated as a homodimer or heterodimer, thereby regulating multiple signaling pathways, including the RAS/RAF/MAPK, AKT, and JAK/STAT pathways, which play essential roles in cell migration, proliferation, and survival [56][57][58]. These pathways are intricately involved in driving cell proliferation and conferring resistance to apoptosis [58].…”

“…EGFR is activated as a homodimer or heterodimer, thereby regulating multiple signaling pathways, including the RAS/RAF/MAPK, AKT, and JAK/STAT pathways, which play essential roles in cell migration, proliferation, and survival [56][57][58]. These pathways are intricately involved in driving cell proliferation and conferring resistance to apoptosis [58]. The overexpression of EGFR leads to an excess of receptors on the cell surface, fostering uncontrolled cell growth and division.…”

Tuning of the Anti-Breast Cancer Activity of Betulinic Acid via Its Conversion to Ionic Liquids

“…In vivo BA mediates the regulation of JAK/STAT, VEGF, EGF/EGFR, TRAIL/TRAIL-R, AKT/mTOR, and ubiquitination pathways, or inhibits some of the transcription factors, thereby reducing the expression of matrix proteinase-2 and -9 (MMP2 and MMP9). It stimulates the expression of the tissue inhibitor of metalloproteinases 2 (TIMP2); inhibits angiogenesis; interferes with the mechanisms of resistance, tumor progression and metastasis; reprograms glucose and lipid metabolism; and reduces the level of tumor-induced proinflammatory cytokines, i.e., modulates the tumor microenvironment [ 21 , 22 ]. In addition, BA can affect estrogen receptor (ER) signaling in ER-positive BC cells [ 23 ].…”