Unravelling the Intricate Mechanism of Cucurbitacin-Mediated Anti-Cancer Therapy

Cancer continues to be a primary cause of death globally, necessitating the constant development of effective and less toxic therapeutics. Cucurbitacins belong to the tetracyclic triterpenoids found mainly in the Cucurbitaceae family. Cucurbitaceae plants exert various biological activities such as anti-diabetic, anti-cancer and anti-inflammatory properties, which make them beneficial in addressing metabolic disorders. This review focuses on cucurbitacins namely A, B, C, D, E, I, IIa, which have been explored in cancer research. Cucurbitacins suppress tumor progression by activating cell death pathways, including apoptosis, autophagy, pyroptosis and ferroptosis. They are known to target multiple crucial biomolecular key players, such as STAT3, AKT, mTOR, ERK, EGFR and TLR4. Additionally, they disrupt cytoskeletal proteins and inhibit cell proliferation, invasion, migration, angiogenesis, and cell-cycle arrest. Cucurbitacins have been demonstrated to modulate tumor microenvironment, leading to enhanced host immune surveillance that reverses traditional therapy resistance from cisplatin, doxorubicin, and paclitaxel. In this review, we highlight the strong potential of cucurbitacins as anti-cancer agents, either as monotherapy or in combination, for the development of safer, cost-effective drugs with improved patient treatment outcomes.