Spermidine as a promising anticancer agent: Recent advances and newer insights on its molecular mechanisms

Spermidine, a naturally occurring polyamine found in semen and various plant sources, displays a wide range of health benefits. Its remarkable anti-inflammatory and antioxidant properties have been documented, along with improvements in respiratory function. The positive charge of spermidine at physiological pH allows interactions with DNA and RNA. Dietary spermidine intake is linked to reduced risks of neurodegeneration, metabolic diseases, heart conditions, and cancer. Spermidine-induced autophagy contributes to slowing cognitive decline by clearing amyloid-beta plaques. It also enhances mitochondrial metabolism and translational activity. The anticancer properties of spermidine are particularly noteworthy, as it's associated with reduced cancer-related mortality. The interplay between tumorigenesis and spermidine involves polyamine metabolism regulation, immune surveillance, apoptosis, and autophagy. Higher polyamine intake suppresses tumor progression. Spermidine has cell-autonomous effects on cancer cells and influences their interactions with immune effectors, facilitating tumor-associated antigen identification and ultimately, cancer cell death. Spermidine-mediated autophagy inhibits apoptosis activation in cancer cells and plays a role in tissue development and cell differentiation.

The review extensively cites various studies examining spermidine's effects. These studies highlight spermidine's impact on autophagy, apoptosis, and the role of spermidine/spermine N1-acetyltransferase (SSAT) in cancer. Specific studies referenced explore spermidine's mechanisms in different cancer types (e.g., hepatocellular carcinoma, colorectal cancer, cervical cancer, breast cancer, prostate cancer, melanoma) and its interactions with existing chemotherapeutic agents.

This is a review article; therefore, it does not involve original research methodology. The authors conducted a comprehensive literature search to identify relevant studies on spermidine's anticancer mechanisms. Information was gathered from peer-reviewed publications and databases, focusing on in vitro and in vivo studies investigating spermidine's effects on cancer cell lines and animal models. The review synthesizes existing knowledge on spermidine's role in autophagy, apoptosis, and the regulation of polyamine metabolism in cancer. The data presented is analyzed and discussed in relation to the established literature on cancer biology and therapeutic strategies.

The review summarizes key findings regarding spermidine's anticancer mechanisms: **Spermidine-induced autophagy:** Spermidine inhibits the acetyltransferase EP300, inducing autophagic flux and removing toxic cellular debris, thus preventing oncogenesis. It enhances autophagy via MAP1S, improving the survival of patients with certain cancers. **Spermidine-induced apoptosis:** Spermidine induces apoptosis in various cancer cells by increasing intracellular ROS, disrupting mitochondrial membrane potential, and releasing pro-apoptotic molecules. Modified spermidine analogues, such as acyl spermidine derivatives and BNIPSpd, exhibit enhanced pro-apoptotic activity. **Spermidine/spermine N1-acetyltransferase (SSAT):** SSAT plays a key role in polyamine homeostasis and acts as a diagnostic marker for human cancers. Modulating SSAT expression, through polyamine analogues like BESPM and DENSpm, enhances the sensitivity of cancer cells to chemotherapeutic agents. This modulation affects cell cycle arrest, particularly at the S-phase, by regulating cyclin A and E2F-1 expression. The review integrates the findings from multiple studies, showcasing the synergistic effects of spermidine and its analogues with established chemotherapeutic agents in various cancers. The observed effects include reduced tumor growth and increased cell death through multiple mechanisms involving apoptosis, autophagy and polyamine metabolism. The influence of spermidine on the immune system, including anticancer immunosurveillance, is also discussed.

The findings of this review strongly support the potential of spermidine as a promising anticancer agent. The multiple mechanisms of action, including autophagy induction, apoptosis initiation, and modulation of polyamine metabolism through SSAT, indicate a multifaceted approach to cancer treatment. The synergistic effects observed when combining spermidine or its analogues with existing chemotherapeutic agents highlight the potential for improved treatment strategies. The identification of SSAT as a key regulatory enzyme and diagnostic biomarker opens further avenues for targeted therapies. The review's compilation of evidence suggests that spermidine warrants further investigation and clinical translation to develop novel anticancer medications.

Spermidine exhibits significant anticancer potential through diverse mechanisms involving autophagy, apoptosis, and polyamine metabolism regulation. Its use in combination with existing chemotherapeutic agents shows promise for enhanced efficacy. Further research should focus on clinical trials to validate these findings and explore the optimal dosage and administration routes for spermidine and its derivatives in various cancer types. Investigating the precise interactions between spermidine and the immune system will further refine its therapeutic application.

As a review article, this study is limited by the available published literature. While the authors performed a comprehensive literature search, some relevant studies may have been overlooked. Further research is needed to fully elucidate the precise mechanisms of action and the optimal therapeutic applications of spermidine in various cancer types and stages. Clinical trials are essential to establish efficacy and safety in humans.