Cucurbitacins as Multifunctional Anticancer Agents: Chemistry, Molecular Mechanisms, Translational Challenges, and Emerging Therapeutic Opportunities

Abstract

Cancer continues to be a significant health challenge worldwide and one of the primary contributors to morbidity and mortality. Despite significant progress in the field of immunotherapy, targeted therapy and molecular oncology, the need for improved and safer anti-cancer drugs remains. For a long time, natural ingredients have been a significant source of novel medications. Among these bioactive substances, Cucurbitacins diverse pharmacological properties have made them very promising as madidates. Cucurbitacins represent a class of extremely oxygenated tetracyclic triterpenoids that are predominantly isolated from Cucurbitaceae plants but also isolated from many other plants and fungi. They have been shown to have potent anti tumour properties in various experiments using different types of cancers, including breast cancer, lung cancer, colon cancer, pancreatic cancer, hepatocellular carcinoma, ovarian cancer, prostate cancer, and skin cancer. The updated discussion builds on the idea of the Cucurbitacins as single cytotoxic agents, but incorporates a more comprehensive perspective on multitarget pharmacology, tumour signalling plasticity and translational oncology. When appropriate, the emphasis changes from descriptive reporting to mechanistic interpretation, comparison to other studies and identification of unanswered questions useful for clinical development.
In this review paper, the chemistry, biosynthesis, pharmacological properties and anticancer activity of cucurbitacins have been briefly discussed, with emphasis on the four main members of the group, namely cucurbitacin Q, I, E and D; and cucurbitacin B. These substances have anticancer effect thru a variety of methods, such as suppression of the JAK/STAT3, PI3K/Akt/mTOR, and NF-κB pathways; activation of autophagy and apoptosis; suppression of angiogenesis; disruption of the cytoskeleton; and control of EMT and cancer stem cells. Overall, cucurbitacins are potential and natural compounds to develop anticancer drugs. Furthermore, recent advances in NDDS, combination strategies with conventional chemotherapeutic agents, pharmacokinetic limitations, safety concerns, and future clinical prospects are discussed. Although substantial preclinical evidence supports the therapeutic value of Cucurbitacins, their clinical development remains constrained by challenges such as poor bioavailability, potential systemic toxicity, and limited clinical evaluation. Taken together, A diverse family of naturally occurring substances with great potential for cancer treatment is cucurbitacins. Continued research integrating medicinal chemistry, molecular pharmacology, nanotechnology, and clinical oncology may facilitate the development of cucurbitacin-based treatments for precision cancer medicine.