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

Spermidine is a natural biomolecule with broad health effects, including anti-inflammatory and antioxidant actions, improved respiratory function, and benefits in metabolic and neurodegenerative conditions. Positively charged at physiological pH, it interacts with DNA and RNA. Dietary spermidine intake is associated with reduced risks of neurodegeneration, metabolic disorders, cardiovascular disease, and cancer. Spermidine-induced autophagy may slow cognitive decline by clearing amyloid-beta plaques and enhances mitochondrial metabolism and translation. Its anticancer effects are of particular interest, being associated with reduced cancer-related mortality in humans. The relationship between tumorigenesis and spermidine involves regulation of polyamine metabolism, immune surveillance, apoptosis, and autophagy. Higher polyamine uptake can suppress tumor progression. Spermidine exerts cell-autonomous effects on cancer cells and modulates interactions with immune effectors to facilitate recognition of tumor-associated antigens, promoting cancer cell death. Spermidine-mediated autophagy can inhibit apoptosis in cancer cells and is linked to tissue development and cell differentiation.

The review synthesizes recent in vitro and in vivo evidence on spermidine’s anticancer mechanisms. Key literature includes: (1) Autophagy induction via EP300 inhibition, with spermidine acting as a competitive inhibitor against acetyl-CoA and activating autophagy-related proteins (ATG5, ATG7, ATG12, BECN1, LC3). In vivo studies report suppression of hepatocellular carcinoma and extended lifespan in mice through MAP1S-mediated autophagy. (2) Cancer cell studies: In HeLa cells, spermidine induces S-phase arrest, autophagy (increased LC3-II/I, Atg5, Beclin 1), and apoptosis. In macrophages, spermidine promotes mtROS-dependent AMPK activation, HIF-1α upregulation, and autophagy, influencing anti-inflammatory M2 polarization. (3) Apoptosis: Polyamine analogues (e.g., acyl spermidine derivatives, bisnaphthalimido-spermidine) trigger apoptosis in multiple cancer models; combination approaches (e.g., 5-FU with DENSPM) synergistically upregulate SSAT, deplete polyamines, and induce apoptosis. Enzymatic generation of cytotoxic aldehydes and peroxides by polyamine oxidases contributes to apoptosis. (4) SSAT and cell cycle: SSAT is central to polyamine catabolism and homeostasis, serving as a biomarker and therapeutic target. Adenoviral SSAT expression induces S-phase arrest and growth inhibition in colorectal cancer cells. Polyamine analogues (e.g., BESPM/DENSpm) induce SSAT, deplete polyamine pools, inhibit growth, and enhance chemosensitivity to agents like oxaliplatin and paclitaxel. Collectively, the literature supports spermidine’s roles in autophagy induction, apoptosis regulation, and modulation of polyamine metabolism and immune surveillance as anticancer mechanisms.

This is a narrative review that collates and discusses findings from prior experimental and preclinical studies. No explicit systematic search strategy, inclusion/exclusion criteria, or meta-analytic methods are described. The authors summarize mechanisms and outcomes from in vitro cell line experiments (e.g., HeLa, HT-29, Caco-2, HCT116, LoVo), in vivo mouse models (e.g., lifespan and hepatocellular carcinoma suppression via MAP1S-mediated autophagy), and studies of polyamine analogues and enzyme modulators (e.g., DENSpm, BESPM, EP300 inhibition, SSAT induction).

- Spermidine induces autophagy by competitively inhibiting the acetyltransferase EP300, reducing acetylation of autophagy proteins and histones; inhibition observed at physiological acetyl-CoA (10 µM) and enhanced at 100 µM, consistent with competitive inhibition. - In vivo, oral spermidine suppressed hepatocellular carcinoma via MAP1S-mediated autophagy; a single intraperitoneal dose of 50 mg/kg in wild-type mice induced autophagy; lifelong oral administration extended mouse lifespan by ~25%, dependent on MAP1S-mediated autophagy. - In HeLa cervical cancer cells, spermidine inhibited proliferation by S-phase arrest, increased apoptosis, and induced autophagy, evidenced by elevated LC3-II/I ratio, Atg5, and Beclin 1 protein levels. - Spermidine modulates macrophage polarization via mtROS production, activating AMPK and upregulating HIF-1α, thereby enhancing autophagy and anti-inflammatory gene expression; partial blockade with a HIF-1α inhibitor suggests HIF-1α involvement. - Polyamine analogues can be pro-apoptotic: acyl spermidine derivatives induced apoptosis in Jurkat cells (up to ~70% at 50 µM for compound 4d) with time- and dose-dependence; lipophilicity influenced cytotoxicity via cellular uptake. - Bisnaphthalimidopropyl spermidine (BNIPSpd) exhibited potent cytotoxicity in colon adenocarcinoma cells (IC50: 1.64 µM in HT-29; 0.15 µM in Caco-2), causing DNA damage at 0.5 µM (4 h) and caspase-3 activation (24 h), consistent with apoptosis. - Combination therapy: 5-fluorouracil (5-FU) with DENSPM synergistically upregulated SSAT, depleted spermidine/spermine, increased acetylated spermidine, activated caspase-9, disrupted mitochondrial membrane potential, and released cytochrome c in HCT116 cells (both p53 wild-type and null), leading to apoptosis. - Enzymatic strategy: Maize polyamine oxidase with exogenous polyamines reduced viability and increased apoptosis in LoVo colon adenocarcinoma cells; mitochondrial depolarization was observed. - SSAT overexpression (AdSAT1) depleted intracellular spermidine/spermine, triggered intrinsic (mitochondrial) apoptosis with loss of mitochondrial membrane potential, downregulation of Bcl-2 family anti-apoptotic proteins, upregulation of Bax, and cytochrome c release; non-SAT1 substrates (α-methylspermidine, N1,N12-dimethylspermine) partially rescued growth and reduced apoptosis, underscoring the role of polyamine depletion. - Polyamine analogues such as BESPM/DENSpm markedly induced SSAT activity (e.g., in MALME-3 melanoma from ~50 to >10,000 pmol/min/mg over 48 h), depleted polyamine pools, and inhibited tumor growth; BESPM administered 3×/day at 10–40 mg/kg for 6 days suppressed established MALME-3 xenografts. - SSAT is a diagnostic biomarker and therapeutic target; its induction enhances chemosensitivity. Combination of DENSpm with oxaliplatin or 5-FU increased responsiveness in resistant colorectal cancer cells; siRNA knockdown of SSAT abrogated synergy. - Overall, spermidine exerts anticancer effects through autophagy induction, apoptosis modulation, regulation of polyamine metabolism (via SSAT and oxidases), and enhancement of anticancer immunosurveillance.

The review addresses how spermidine and related polyamine biology can be leveraged against cancer by integrating multiple mechanistic axes. By inhibiting EP300, spermidine deacetylates key autophagy players, initiating autophagic flux that clears toxic cellular components, reduces oncogenic stress, and may improve antitumor immunosurveillance. In vivo, MAP1S-dependent autophagy mediates tumor suppression and longevity benefits, highlighting a mechanistically coherent autophagy pathway relevant to cancer prevention and therapy. Concurrently, spermidine and its analogues modulate apoptotic pathways. Depending on context, spermidine can either protect from ROS-mediated damage or, in combination with agents that perturb polyamine metabolism or mitochondrial function, facilitate intrinsic apoptosis (e.g., cytochrome c release, caspase activation). Upregulation of SSAT depletes spermidine/spermine, leading to growth arrest (S-phase) and apoptotic priming; pharmacologic or genetic SSAT activation synergizes with conventional chemotherapies (5-FU, oxaliplatin, paclitaxel), overcoming resistance in several models. These mechanisms together explain the observed suppression of proliferation, induction of cell-cycle arrest, and apoptosis in diverse cancer models. The findings position spermidine both as a direct modulator of tumor cell biology and as an adjuvant that reprograms polyamine metabolism to sensitize tumors to cytotoxic agents. However, context dependency is evident; polyamines can support cell growth under certain conditions, and spermidine’s dual antioxidant/oxidant-related effects necessitate careful therapeutic design. Translational emphasis should include biomarker-driven strategies (e.g., SSAT expression/activity) to predict response and guide combination regimens.

The review consolidates evidence that spermidine possesses significant anticancer potential through induction of autophagy (via EP300 inhibition and MAP1S activation), modulation of apoptosis, and regulation of polyamine metabolism centered on SSAT. Polyamine analogues and enzyme-targeting strategies deplete polyamine pools, inhibit proliferation, induce S-phase arrest, and enhance chemosensitivity across multiple cancer types (colon, hepatocellular, breast, prostate, melanoma, glioblastoma). Chemically modified spermidine derivatives show promise as diagnostic/prognostic tools and therapeutics. While increased spermidine intake may support cellular homeostasis and suppress tumorigenesis, polyamines can also support growth of established tumors in some contexts, underscoring the need for precision approaches. Future research should prioritize clinical translation with well-designed trials, standardized dosing, assessment of SSAT as a biomarker, optimization of combination therapies, and deeper investigation into immunosurveillance and context-specific effects.

- The article is a narrative review without a stated systematic search strategy, selection criteria, or risk-of-bias assessment, which may introduce selection bias. - Most evidence is preclinical (in vitro cell lines and animal models); clinical efficacy, safety, and optimal dosing of spermidine or its analogues in cancer patients remain to be established. - Context-dependent effects of polyamines (including potential support of established tumor growth) complicate generalizability and necessitate careful patient selection and therapeutic design. - Heterogeneity of models, dosing regimens, and endpoints across cited studies limits direct comparison and quantitative synthesis. - Biomarker strategies (e.g., SSAT activity) require clinical validation for predictive utility.