The potential roles of gossypol as anticancer agent: advances and future directions

Abstract

Gossypol, a polyphenolic aldehyde derived from cottonseed plants, has seen a transformation in its pharmaceutical application from a male contraceptive to a candidate for cancer therapy. This shift is supported by its recognized antitumor properties, which have prompted its investigation in the treatment of various cancers and related inflammatory conditions. This review synthesizes the current understanding of gossypol as an anticancer agent, focusing on its pharmacological mechanisms, strategies to enhance its clinical efficacy, and the status of ongoing clinical evaluations.The methodological approach to this review involved a systematic search across several scientific databases including the National Center for Biotechnology Information (NCBI), PubMed/MedLine, Google Scholar, Scopus, and TRIP. Studies were meticulously chosen to cover various aspects of gossypol, from its chemical structure and natural sources to its pharmacokinetics and confirmed anticancer efficacy. Specific MeSH terms and keywords related to gossypol's antineoplastic applications guided the search strategy.Results from selected pharmacological studies indicate that gossypol inhibits the Bcl-2 family of anti-apoptotic proteins, promoting apoptosis in tumor cells. Clinical trials, particularly phase I and II, reveal gossypol's promise as an anticancer agent, demonstrating efficacy and manageable toxicity profiles. The review identifies the development of gossypol derivatives and novel carriers as avenues to enhance therapeutic outcomes and mitigate adverse effects.Conclusively, gossypol represents a promising anticancer agent with considerable therapeutic potential. However, further research is needed to refine gossypol-based therapies, explore combination treatments, and verify their effectiveness across cancer types. The ongoing clinical trials continue to support its potential, suggesting a future where gossypol could play a significant role in cancer treatment protocols.

Keywords: Anticancer mechanisms; Apoptosis; Gossypol; Mechanisms; Molecular targets; Proliferation.

Fig. 1

Structure of gossypol enantiomers: ( +)-gossypol and (-)-gossypol

Fig. 2

Chemical structure of tautomers of gossypol [38]

Fig. 3

Structures of some gossypol derivatives

Fig. 4

Apoptosis induction in cancer cells by gossypol. Gossypol interferes with cellular function by causing mitochondrial dysfunction, which leads to an increase in reactive oxygen species (ROS). This accumulation of ROS results in oxidative stress that damages cellular components, including DNA. Concurrently, gossypol's interaction with mitochondria leads to ATP depletion, crippling the cell’s energy supply and further exacerbating cellular stress. The compound also hinders key survival signals by downregulating Akt, a protein essential for cell survival, and c-Myc, a transcription factor that supports cell growth and proliferation. Additionally, gossypol inhibits the activity of telomerase reverse transcriptase (TERT), an enzyme vital for maintaining telomere length and thereby cell longevity. Together, these actions culminate in the activation of the cell’s apoptotic pathways, leading to programmed cell death. ↑ increase, ↓ decrease, telomerase reverse transcriptase (TERT), Adenosine triphosphate (ATP), Cellular myelocytomatosis oncogene (c-MyC), serine/threonine protein kinase (Akt)

Fig. 5

Autophagy induced by gossypol in cancer cells. Gossypol stimulates the conversion of LC3-I to its lipidated form LC3-II, which is a key step in autophagy initiation. LC3-II is associated with the autophagosome membrane. The process begins with the initiation of a phagophore, which expands to engulf cellular components targeted for degradation. The maturation of the phagophore leads to the formation of an autophagosome, which then fuses with a lysosome to form an autolysosome. Within the autolysosome, the encapsulated materials are degraded and recycled, providing the cell with a mechanism to remove damaged organelles and proteins. The action of gossypol in promoting this pathway suggests a potential therapeutic mechanism by which cancer cell survival is reduced through the enhanced turnover of cellular components. LC3-I Microtubule-associated proteins 1A/1B light chain 3B, form I, LC3-II Microtubule-associated proteins 1A/1B light chain 3B, form II, PE Phosphatidylethanolamine

Fig. 6

Illustrative diagram related to mechanisms of gossypol-induced decrease in cancer cell viability. The figure illustrates the multifaceted mechanisms by which gossypol reduces the viability of cancer cells. Gossypol inhibits TNF-α, which in turn prevents the activation of NF-kB, a transcription factor that regulates genes responsible for cell survival and proliferation. Additionally, gossypol disrupts the Nrf2/ARE pathway within the nucleus, leading to decreased DNA transcription of survival genes. It also inhibits the ICAM-1 pathway, contributing to reduced inflammation and interference with cancer cell adhesion. Gossypol's interaction with CUL4 appears to promote the degradation of survival proteins, further inducing cell death. Moreover, it suppresses NOXA, a pro-apoptotic protein, and induces the generation of ROS, leading to oxidative stress and damage. Collectively, these actions lead to a decrease in cancer cell viability. ARE Antioxidant Response Element, CUL4 Cullin 4, ICAM-1 Intercellular Adhesion Molecule 1, IL-6 Interleukin 6, NF-kB Nuclear Factor kappa-light-chain-enhancer of activated B cells, NOXA Phorbol-12-myristate-13-acetate-induced protein 1, Nrf2 Nuclear Factor Erythroid 2–Related Factor 2, ROS Reactive Oxygen Species, TLR4 Toll-Like Receptor 4, TNF-α Tumor Necrosis Factor alpha. Symbols: ↓decrease, X inhibition

Fig. 7

Inhibition of angiogenesis in tumor cells by gossypol.  It exerts this  therapeutic effect by downregulating the expression of vascular endothelial growth factor (VEGF), a critical protein that stimulates the formation of new blood vessels (angiogenesis) within tumor tissues. The suppression of VEGF leads to a decrease in new blood vessel formation, effectively starving the tumor of the necessary nutrients and oxygen needed for growth. Additionally, gossypol interferes with the MDM2 protein within the nucleus. MDM2 is known to negatively regulate the tumor suppressor p53, and by inhibiting MDM2, gossypol may contribute to the reactivation of p53's tumor-suppressive functions. Through these mechanisms, gossypol effectively inhibits tumor angiogenesis, contributing to its anticancer effects. VEGF Vascular Endothelial Growth Factor, MDM2 Mouse Double Minute 2 Homolog