Curcumin in prostate cancer: a systematic review of molecular mechanisms and nanoformulated therapeutic strategies

Abstract

Background

Prostate cancer (PCa) is one of the most prevalent malignancies in men, often progressing to castration-resistant forms and resisting conventional therapies. Curcumin, a polyphenol from Curcuma longa, has emerged as a potent anti-cancer agent by modulating several molecular pathways.

Objective

This systematic review seeks to synthesize current preclinical evidence on the molecular mechanisms underlying curcumin's effects in PCa and to evaluate nanoformulation strategies developed to enhance its pharmacokinetics and therapeutic efficacy.

Methods

A comprehensive search of five major databases up to March 1, 2025 identified 22 eligible studies on curcumin and PCa. Data on molecular pathways, therapeutic outcomes, and delivery systems were extracted and assessed using ToxRTool and SYRCLE guidelines.

Results

Curcumin modulated key pathways including PI3K/Akt/mTOR (8 studies), NF-κB (7), AR signaling (6), and apoptosis-related regulators (13). Therapeutic outcomes included apoptosis, necroptosis, cell cycle arrest, and suppression of migration and angiogenesis. Nanoformulations (e.g., Theracurmin®, PLGA-curcumin) demonstrated improved bioavailability and tumor-targeted delivery. Synergistic combinations with docetaxel, quercetin, or phototherapy enhanced its anti-cancer effects.

Conclusion

Curcumin exerts multi-targeted anticancer effects in PCa models, but clinical translation is hindered by poor bioavailability. Advanced nanoformulations and rational combination therapies offer promising strategies to overcome these limitations. Clinical trials evaluating optimized curcumin delivery systems in well-defined PCa populations are strongly recommended.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12885-025-15152-2.

Introduction

Prostate cancer (PCa) is one of the most prevalent malignancies and a major cause of cancer-related mortality among men globally, accounting for a significant proportion of the global cancer burden [1]. Despite initial responsiveness to androgen deprivation therapy, many patients progress to castration-resistant prostate cancer (CRPC), which is associated with poor prognosis and limited treatment options [2].

Curcumin, a naturally occurring polyphenolic compound extracted from the rhizome of Curcuma longa, has attracted significant attention for its pleiotropic pharmacological properties, including anti-inflammatory, antioxidant, and anticancer activities [3]. Unlike conventional chemotherapeutic agents, curcumin can simultaneously modulate several critical oncogenic signaling pathways implicated in PCa pathogenesis, such as PI3K/Akt/mTOR, NF-κB, Wnt/β-catenin, STAT3, and androgen receptor (AR) signaling [4–6].

Numerous preclinical studies have demonstrated that curcumin suppresses cell proliferation, induces apoptosis and necroptosis, inhibits angiogenesis and epithelial–mesenchymal transition (EMT), and sensitizes cancer cells to chemo- and radiotherapy [6, 7]. These effects are particularly relevant for overcoming drug resistance and metastatic progression in aggressive forms of PCa [8].

However, curcumin’s therapeutic application is hindered by poor aqueous solubility, rapid metabolism, and limited systemic bioavailability [9]. To address these limitations, several nanotechnology-based delivery platforms—such as liposomes, polymeric nanoparticles, and hybrid nanocarriers—have been developed to enhance curcumin’s pharmacokinetic profile and improve its therapeutic index [10].

This systematic review synthesizes current preclinical evidence regarding the molecular mechanisms of curcumin in prostate cancer models and to explore recent advances in curcumin nanoformulations. By integrating mechanistic insights with innovative delivery strategies, this review highlights the translational potential of curcumin as a multi-targeted therapeutic agent in prostate cancer management.

To the best of our knowledge, this is the first systematic review dedicated exclusively to prostate cancer that not only synthesizes mechanistic evidence but also integrates advances in nanoformulation-based therapeutic strategies. This dual perspective differentiates our work from previous general reviews on curcumin and provides novel insights for translational applications in prostate cancer.

Material and methods

Search strategy

A comprehensive and systematic search was conducted in PubMed, Scopus, Web of Science, Embase, and Google Scholar databases from inception to March 1, 2025. The following search terms were used in combination: “curcumin” OR “Curcuma longa” AND “prostate cancer” OR “prostatic carcinoma” OR “prostate neoplasm” AND “anticancer” OR “molecular pathways” OR “nanoparticles” OR “therapeutic strategies”. Boolean operators (AND, OR) and truncations were applied to optimize sensitivity. No language restrictions were imposed, but only peer-reviewed original articles were considered.

Eligibility criteria

Studies were included if they: (1) evaluated curcumin or curcumin-based formulations in prostate cancer models (cell lines, animal models, or human tissues); (2) reported outcomes related to molecular mechanisms (e.g., apoptosis, migration, signaling pathways); and (3) used clearly described experimental methods. Exclusion criteria were: reviews, conference abstracts, non-English articles, studies on other cancers without separate PCa data, or those lacking mechanistic relevance.

Study selection

Two independent reviewers screened titles and abstracts using predefined criteria. Full texts of potentially eligible studies were then assessed. Disagreements were resolved by a third reviewer. The PRISMA 2020 guidelines were followed, and a flowchart (Fig. 1) was used to document the selection process.

Fig. 1.

PRISMA flow diagram illustrating the process of study identification, screening, eligibility assessment, and inclusion in the systematic review. The literature search was conducted up to March 1, 2025

Data extraction

A standardized data extraction form was used to collect the following variables: article title, year of publication, model system (cell line/animal/human), curcumin dose and duration, molecular pathways targeted, mechanistic findings, therapeutic outcomes (e.g., apoptosis, migration), delivery system (if applicable), and key results. Extraction was independently performed by two reviewers and cross-verified for accuracy.

Quality assessment

In vitro and in vivo studies were assessed using a modified ToxRTool, which evaluates clarity of objectives, reproducibility of methods, and biological relevance. Animal studies were additionally evaluated with the SYRCLE Risk of Bias tool to account for randomization, blinding, and allocation concealment. When clinical studies were included, the Joanna Briggs Institute (JBI) checklist or the Cochrane RoB 2.0 tool was applied as appropriate.

Based on these criteria, each study was categorized as high (≥75%), moderate (50–74%), or low quality (<50%). The distribution of quality scores is summarized in Table 1. Out of the 22 included studies, 17 (77%) were rated as high quality, demonstrating well-defined objectives, reproducible methodologies, and appropriate model systems. The remaining 5 studies (23%) were categorized as moderate quality, often due to incomplete reporting of controls, limited replication, or lack of methodological transparency. Importantly, no study was classified as low quality.

Table 1.

Quality Assessment Summary Table 1

Study	Study Type	Assessment Tool Used	Score (% criteria met)	Quality Level
Chen et al. (2020) [12]	In vitro/In vivo	ToxRTool + SYRCLE	90%	High
Kazantzis et al. (2020) [26]	In vitro	ToxRTool	75%	High
Cheng et al. (2020) [27]	In vitro/In vivo	ToxRTool + SYRCLE	85%	High
Mapoung et al. (2020) [20]	In vitro/In vivo	ToxRTool + SYRCLE	78%	High
De Velasco et al. (2020) [11]	In vitro/In vivo	ToxRTool + SYRCLE	88%	High
Ossikbayeva et al. (2021) [25]	In vitro	ToxRTool	80%	High
Lee et al. (2021) [15]	In vitro	ToxRTool	82%	High
Pan et al. (2021) [17]	In vitro/Clinical	ToxRTool + JBI	76%	High
Bevacqua et al. (2021) [16]	In vitro	ToxRTool	79%	High
Rutz et al. (2021) [19]	In vitro	ToxRTool	74%	Moderate
Nakayama et al. (2021) [14]	In vitro	ToxRTool	77%	High
Al-Rabia et al. (2022) [13]	In vitro	ToxRTool	81%	High
Costantini et al. (2022) [28]	In vitro	ToxRTool	73%	Moderate
Boccellino et al. (2022) [23]	In vitro	ToxRTool	75%	High
Alhasawi et al. (2022) [29]	In vitro	ToxRTool	70%	Moderate
Woźniak et al. (2023) [30]	In vitro	ToxRTool	68%	Moderate
Panahizadeh et al. (2023) [31]	In vitro	ToxRTool	80%	High
Pellegrino et al. (2023) [24]	In vitro	ToxRTool	77%	High
Pellegrino et al. (2024) [21]	In vitro	ToxRTool	79%	High
Tossetta et al. (2025) [18]	In vitro	ToxRTool	74%	Moderate
Yakubu et al. (2025) [22]	In vitro	ToxRTool	83%	High

Results

A total of 22 studies met the eligibility criteria, including 20 in vitro investigations, of which 10 also incorporated in vivo xenograft or transgenic models. The majority of studies evaluated curcumin or its nanoformulations on established prostate cancer cell lines such as PC-3, DU145, LNCaP, and 22Rv1. Table 2 provides a comprehensive overview of the characteristics and major findings of the included studies, while the following subsections present a narrative synthesis of the main outcomes.

Table 2.

Summary of included studies evaluating the molecular mechanisms and therapeutic outcomes of curcumin and its nanoformulations in prostate cancer models

Article Title	Publication Year	Model System (Cell line/Animal/Human)	Curcumin Dose & Duration	Molecular Pathways Targeted	Mechanistic Findings	Therapeutic Outcomes (e.g., apoptosis, angiogenesis)	Delivery System (e.g., nanoparticles)	Key Results	References
Anti prostate cancer therapy: Aptamer-functionalized, curcumin and cabazitaxel co-delivered, tumor targeted lipid-polymer hybrid nanoparticles	2020	Cell lines: LNCaP (PSMA+), PC3 (PSMA−); Animal model: LNCaP xenograft mice	In vitro: 0.1–100 µM (72 h); In vivo: CUR (2 mg/kg) + CTX (5 mg/kg) (IV, every 3 days)	PSMA, PI3K/AKT, NF-κB, Apoptosis Pathways	Aptamer-functionalization enhances tumor targeting, prolonged drug retention, and synergy between curcumin and cabazitaxel	Increased apoptosis, tumor suppression, improved drug accumulation	Aptamer-functionalized Lipid-Polymer Hybrid Nanoparticles (APT-CUR/CTX-LPNs)	APT-CUR/CTX-LPNs exhibit superior tumor inhibition compared to free drug and non-functionalized nanoparticles	[12]
Curcumin derivatives as photosensitizers in photodynamic therapy: photophysical properties and in vitro studies with prostate cancer cells	2020	LNCaP (prostate cancer cell line)	3 µM for 1 hour pre-irradiation	ROS generation, intracellular uptake and localization	High ROS production (compounds 2 & 3); compound 4 showed red-shifted absorption and highest photostability; intracellular accumulation (especially for 2 & 4)	Apoptosis, reduced viability post-PDT; biphasic vs dose-dependent photodynamic effect	None (free compound, dissolved in DMSO)	Curcuminoids 2 and 4 had significant PDT efficacy, with short LD50; 1 and 3 showed biphasic light-dose response	[26]
The Curcumin Derivative, H10, Suppresses Hormone-Dependent Prostate Cancer by Inhibiting 17β-Hydroxysteroid Dehydrogenase Type 3	2020	In vitro: LC540 cells overexpressing 17β-HSD3, Rat testicular microsomes; In vivo: LNCaP xenografts in nude mice; male Sprague-Dawley rats	In vitro: 0.25–1 µM for 24–48 h; Ex vivo: 10–40 µM; In vivo: 10–50 mg/kg H10 i.p. daily for 7 days	17β-HSD3 enzyme activity (testosterone biosynthesis); downstream AR signaling	H10 inhibited testosterone production by direct enzymatic inhibition of 17β-HSD3 without altering its expression; no effect on CYP11A1, CYP17A1, 3β-HSD1, STAR; androgen-driven tumor suppression	Significant inhibition of tumor growth in LNCaP xenografts; dose-dependent testosterone suppression; minimal systemic toxicity; reduced Ki-67 and CD31; induced tumor necrosis	Free compound in 10% DMSO + methylcellulose; intraperitoneal injection	H10 dose-dependently suppressed androgen production and tumor progression; had no adverse effects on body/testis weights in rats; did not affect upstream steroidogenic enzymes	[27]
Dehydrozingerone, a Curcumin Analog, as a Potential Anti-Prostate Cancer Inhibitor In Vitro and In Vivo	2020	In vitro: PLS10 (rat CRPC); In vivo: PLS10 xenograft in BALB/c-nu/nu mice	In vitro: DZG 0–200 µM (48 h), IC50 ≈ 153 µM; In vivo: 30 mg/kg BW i.p., 2×/week for 5 weeks	Cell cycle (cyclin D1), angiogenesis (CD31)	↓Cyclin D1 → G1 arrest; ↓CD31+ area → ↓angiogenesis; ↑tumor apoptosis (non-sig.)	↓Cell proliferation, ↓angiogenesis, mild ↑apoptosis; significant ↓tumor volume in vivo	Not nanoparticle-based; intraperitoneal injection of synthesized DZG	DZG >CUR in vivo efficacy due to ↑bioavailability and tissue retention; DZG detectable up to 3 h post-injection; improved PK/PD profile vs. curcumin	[20]
Chemopreventive effects of nanoparticle curcumin in a mouse model of Pten-deficient prostate cancer	2020	In vitro: Mouse prostate cancer cell lines (7113-D3, castration-naïve; 2945-E10, castration-resistant) <br>In vivo: Pten-deficient conditional transgenic mouse model	In vitro: 5–15 µM up to 96 h <br>In vivo: 76 or 380 mg/kg/day for up to 16 weeks	PI3K/AKT signaling pathway (via PTEN loss); cell proliferation (Ki-67); apoptosis (caspase-3)	Theracurmin (nanoparticle curcumin) reduced cell viability dose-dependently; in vivo, it suppressed Ki-67 proliferation index at 12 and 16 weeks without significantly inducing apoptosis	Reduced cell viability in vitro; decreased cancer cell proliferation in early-stage prostate cancer in vivo; no significant apoptosis induction	Nanoparticle formulation (Theracurmin; enhanced bioavailability >40-fold vs. conventional)	Chemopreventive potential in early-stage prostate cancer; histological signs of reduced PIN progression; accumulation in liver noted	[11]
Curcumin and Carnosic Acid Cooperate to Inhibit Proliferation and Alter Mitochondrial Function of Metastatic Prostate Cancer Cells	2021	Human metastatic prostate cancer cell lines (DU145, PC-3)	Curcumin (5–7 µM) and Carnosic Acid (1–5 µM); 24–48 h; 7 days for clonogenic assay	SGK1/mTOR; cell cycle regulators (Cyclin D1/E, CDK2/4, p21, p27); mitochondrial OxPhos; calcium signaling	Combination treatment caused G0/G1 cell cycle arrest; suppressed mitochondrial membrane potential; downregulated SGK1 expression and Ser422 phosphorylation; transient calcium influx; altered OxPhos complexes I–IV	Inhibited proliferation, suppressed clonogenic growth; induced cell cycle arrest without apoptosis; mitochondrial dysfunction	No delivery system (free compounds used in vitro)	Synergistic antiproliferative effect at low concentrations without triggering ROS or cell death; effective in DU145 >PC-3	[25]
Curcumin Targets Both Apoptosis and Necroptosis in Acidity-Tolerant Prostate Carcinoma Cells	2021	PC-3 and lactic acid-adapted PC-3AcT (human prostate cancer), RWPE-1 and HPrEC (normal epithelial) cell lines; 2D monolayer and 3D spheroid cultures	Curcumin 0–160 µM; 48 h	ROS generation; mitochondrial dysfunction; ATP depletion; DNA damage (ATM/ATR–CHK1/CHK2); apoptosis (caspase-3, PARP, Bax/Bcl-2); necroptosis (RIP3/MLKL)	Curcumin induced strong ROS generation, loss of mitochondrial membrane potential, DNA damage, ATP depletion; activated both apoptosis and necroptosis; effects reversed by NAC (ROS scavenger) and ATP supplementation	Induced cell death via apoptosis and necroptosis; decreased viability in spheroids; preferential toxicity to PC-3AcT cells	Free compound (no delivery system)	Curcumin induced dual cell death pathways via oxidative mitochondrial dysfunction and energy depletion, especially effective in acidic-tolerant prostate cancer cells; minimal effect on normal prostate cells	[15]
Curcumin inhibits prostate cancer progression by regulating the miR-30a-5p/PCLAF axis	2021	Human prostate cancer cell lines (PC-3, DU145); Human tissues (clinical samples from 35 patients)	10–50 µmol/L for 12–48 h (30 µmol/L most effective); 24 h commonly reported	miR-30a-5p/PCLAF axis; apoptosis-related proteins (Bax, Bcl-2, caspase-3); cell cycle and migration pathways	Curcumin upregulated miR-30a-5p and suppressed PCLAF expression; enhanced apoptosis markers (Bax↑, cleaved caspase-3↑, Bcl-2↓); inhibited proliferation, migration, and invasion	Time- and dose-dependent suppression of cell viability; apoptosis induction; suppression reversed by miR-30a-5p inhibition	Dissolved in DMSO (no nanoparticles or advanced delivery system used)	Curcumin suppressed prostate cancer progression via miR-30a-5p-mediated downregulation of PCLAF; functional rescue seen with miR-30a-5p inhibitor	[17]
Dextran-Curcumin Nanosystems Inhibit Cell Growth and Migration Regulating the Epithelial to Mesenchymal Transition in Prostate Cancer Cells	2021	PC-3 (prostate cancer cells), PNT-2 (normal prostate cells)	5, 10, 20 µM equivalent CUR; 24–48 h	ROS generation, EMT pathway (ZEB1, vimentin, E-cadherin), cell cycle (G2/M), apoptosis	Induction of apoptosis, G2/M arrest, suppression of EMT via downregulation of ZEB1 and vimentin, upregulation of E-cadherin	Apoptosis, cell cycle arrest, reduced migration, enhanced ROS production	Dextran-curcumin self-assembled nanoparticles (DEX/CUR); also DEX/CUR@DOXO	DEX/CUR showed enhanced ROS and cytotoxicity vs free CUR; targeted DOXO delivery with pH-responsive release; synergistic cytotoxicity in PC-3 cells	[16]
Growth, Proliferation and Metastasis of Prostate Cancer Cells Is Blocked by Low-Dose Curcumin in Combination with Light Irradiation	2021	Prostate cancer cell lines: DU145 and PC3	0.1–0.4 µg/mL CUR; 5 min light irradiation (1.65 J/cm2); observed up to 72 h	CDK1, CDK2, Cyclin A/B, pCDK1/2, Akt/pAkt, Rictor/pRictor, Raptor/pRaptor, ILK, FAK/pFAK, Integrins (αv, α5, α6, β1–β4), CD44	Suppression of CDK-cyclin axis, G2/M arrest, Akt-mTOR inhibition, downregulation of integrins and CD44	- Significant reduction in cell growth, proliferation, and clonogenicity. - Increased apoptosis (early and late). - Cell cycle arrest (increase in G2/M, decrease in G0/G1 and S phases). - Reduced adhesion and migration.	None specified; light-activated enhancement strategy	Light+Curcumin strongly enhanced anti-tumor effects vs. either alone; selectively suppressed proliferation and metastasis; affected multiple signaling axes at low CUR doses	[19]
Effects of Curcumin Combined With the 5-alpha Reductase Inhibitor Dutasteride on LNCaP Prostate Cancer Cells	2021	LNCaP prostate cancer cells (AR-positive)	10–50 µM CUR; 10 µM dutasteride; 6–72 h (depending on assay)	Androgen signaling, steroidogenesis (AKR1C2, CYP17A1, SRD5A1/2), DNA damage response (ATM, γ-H2AX), apoptosis (PARP)	↓Testosterone & DHT via ↑AKR1C2 expression; ↓AR; ↑DNA damage (p-ATM, γH2AX); ↑apoptosis via caspase-3/7 and cleaved PARP	↓Viability, proliferation, PSA secretion; ↑apoptosis and DNA damage markers	Theracurmin® (nano-curcumin) used, but no novel delivery system developed in vitro	Combination therapy more effective than single agents in ↓androgens, ↑DNA damage, ↓PSA (up to 70%); additive but not fully synergistic	[14]
Boosting curcumin activity against human prostatic cancer PC3 cells by utilizing scorpion venom conjugated phytosomes	2022	Human PC3 prostate cancer cells (in vitro)	CUR-PL-SV IC₅₀: 3.3 µg/mL; compared to CUR alone (32.1 µg/mL) and PL-SV (12.3 µg/mL); 48 h exposure	Bax, p53, caspase-3, Bcl-2, NF-κB, TNF-α; Mitochondrial membrane potential	↑ Bax, ↑ p53, ↑ Caspase-3, ↓ Bcl-2, ↓ NF-κB, ↓ TNF-α, ↓ MMP, ↑ apoptosis	G2/M and pre-G1 cell cycle arrest; increased apoptosis and necrosis; reduced proliferation; mitochondrial dysfunction	Scorpion venom-conjugated phytosomes (CUR–PL–SV)	CUR-PL-SV showed superior anticancer efficacy vs. CUR or PL-SV; enhanced apoptosis, cell cycle arrest, and anti-inflammatory effects	[13]
Effects of Curcumin and Lactoferrin to Inhibit the Growth and Migration of Prostatic Cancer Cells	2022	DU145 and PC3 prostate cancer cell lines (androgen-resistant)	Curcumin: 2.5 & 5 µg/mL; Lactoferrin: 175 µM; for 24 h	Akt phosphorylation; DR4/DR5; Integrins (α3, β1); Annexin V	CU and LF (alone and in combo) downregulated integrin α3/β1, upregulated DR4/DR5 and annexin V, reduced p-Akt levels	Reduced proliferation and migration (via MTT, scratch, qPCR); increased apoptosis (ELISA, WB); synergy in combined treatment	Free compound in culture media; no nano-carrier used	CU+LF synergistically inhibited migration, integrin expression, and promoted apoptosis via extrinsic and intrinsic pathways	[28]
The Role of Curcumin in Prostate Cancer Cells and Derived Spheroids	2022	DU145 (moderate metastasis) and PC-3 (high metastasis) prostate cancer cell lines; 3D spheroids in Matrigel	1.72–55.2 µg/mL (4.67–149.85 μM) for 24–72 h in 2D; 6.9 µg/mL (18.73 µM) for 10–15 days in 3D culture	EGFR/ERK signaling pathway	Curcumin reduced EGFR expression and ERK activation; enhanced cytotoxicity when combined with chemotherapeutic agents (cisplatin, paclitaxel, docetaxel)	Apoptosis; reduced viability; reduced organoid size; synergy with chemo drugs	Free compound dissolved in DMSO	Curcumin alone reduced viability and spheroid size significantly, comparable to chemotherapy drugs; synergistic enhancement with docetaxel, paclitaxel, and cisplatin (especially in DU145); apoptosis confirmed by TUNEL and Ki-67 downregulation	[23]
Curcumin and Its Derivatives Induce Apoptosis in Human Cancer Cells by Mobilizing and Redox Cycling Genomic Copper Ions	2022	Human prostate cancer cell lines (PC3, LNCaP, DU145, C42B), normal breast epithelial cells (MCF-10A); Peripheral human lymphocytes	0–30 µM for 72 h (cell assays); 25 µM for mechanistic assays	Redox cycling of genomic copper; ROS generation; CTR1 and ATP7A expression	Curcumin mobilizes endogenous copper, leading to ROS production and oxidative DNA damage; effect attenuated by copper chelator (neocuproine) and ROS scavengers	Inhibition of proliferation; Apoptosis induction; Reduced colony formation and migration	Native form dissolved in DMSO (up to 0.1% v/v), no advanced delivery	Curcumin selectively induces apoptosis in cancer cells via copper-mediated oxidative stress; non-toxic to normal cells unless copper-supplemented	[29]
The Effect of Natural Substances Contained in Bee Products on Prostate Cancer in In Vitro Studies	2023	Human prostate cancer cell line (LNCaP)	10–100 µM for 24 and 48 h	Mitochondrial pathway, lysosomal activity, protein synthesis modulation, ROS production	Dose- and time-dependent cytotoxicity; curcumin induced mitochondrial and lysosomal dysfunction, oxidative stress, and morphological signs of necrosis	Inhibition of proliferation; decreased mitochondrial and lysosomal activity; protein synthesis suppression	Native curcumin dissolved in DMSO; no advanced delivery system used	Curcumin showed strong lysosomal inhibition and induced cellular vacuolization suggesting necrotic effects; IC₅₀ (48 h, XTT): 48.8 µM	[30]
Cytotoxicity of curcumin against CD44⁺ prostate cancer cells: Roles of miR-383 and miR-708	2023	Human prostate cancer cell line (PC3), CD44+ (cancer stem cells) and CD44- (non-CSCs) sorted by MACS	CD44⁻: 15–60 µM; CD44⁺: 50–150 µM; 48 hr exposure	miR-383-5p → LDHA, PRDX3; miR-708-5p → RAP1B, LSD1	Curcumin upregulated miR-383 and miR-708 levels; downregulated their target oncogenes; altered nuclear morphology; induced apoptosis	↑ Apoptosis, nuclear shrinkage, autophagy; ↓ cell viability (IC50: CD44⁻ = 40.3 µM, CD44⁺ = 83.3 µM)	Free curcumin (DMSO-based)	CD44⁺ cells showed higher resistance to curcumin (IC₅₀ ≈ 83 µM) vs. CD44⁻ (IC₅₀ ≈ 40 µM); curcumin significantly induced apoptosis, promoted miRNA expression, and downregulated oncogenic targets such as LDHA, PRDX3, RAP1B, and LSD1	[31]
Enhancing the Anticancer and Anti-Inflammatory Properties of Curcumin in Combination with Quercetin, for the Prevention and Treatment of Prostate Cancer	2023	Human (PC-3 prostate cancer cell line), Mouse (RAW 264.7 macrophages)	Curcumin 5–20 µM (24–48 h); selected for synergy at 10 µM CUR + 10 µM QRT	ROS generation, cell cycle regulation, apoptosis, NF-κB, MAPK, ERK, PI3K/Akt, pro-inflammatory cytokines (TNF-α, IL-6, IL-1β)	CUR → G2/M arrest; QRT → S arrest; Combined → ↑ apoptosis, ↑ ROS, ↓ inflammatory cytokines	↓ Cell viability, ↑ Apoptosis, ↑ ROS, ↓ NO, ↓ IL-6, IL-1β, TNF-α	Free-form (DMSO diluted), not nanoparticle-based	CUR + QRT synergistically enhanced antiproliferative and anti-inflammatory effects compared to single agents	[24]
Modulation of energetic and lipid pathways by curcumin as a potential chemopreventive strategy in human prostate cancer cells	2024	PC-3, LNCaP (Prostate Cancer Cell Lines), PNT-2 (Normal Prostate Cell Line)	1 and 5 µM CUR for 24–48 h	Energy metabolism (glycolysis, OxPhos); Lipid metabolism (SREBP1/2, FASN, LDL-R, HMGCR, etc.); PDHA1 signaling	Binds to PDHA1 enzyme; decreases OxPhos; increases glycolysis; downregulates lipogenesis genes	Apoptosis (indirectly suggested via mitochondrial dysfunction); inhibition of lipogenesis; reprogramming of cancer metabolism	Free Curcumin in DMSO used	- CUR reduces maximal respiration and mitochondrial membrane potential in PC-3 cells - CUR increases glycolysis and glycolytic reserve in PC-3 - CUR downregulates lipid metabolism genes - Molecular docking: CUR binds PDHA1 with high affinity (−8.2 kcal/mol) - Minimal effects in normal PNT-2 cells	[21]
Dose-dependent effects of curcumin on 22Rv1 prostate cancer cell line	2025	Human prostate cancer cells (22Rv1)	5, 15, and 30 μM for 24 h	Cell cycle (G2/M arrest), p21/p16 expression, caspase-3 activation	All doses caused G2/M arrest; 15 & 30 μM induced apoptosis (cleaved caspase-3); p21 expression increased at all doses, p16 only at 30 μM	Senescence-like phenotype at 5 μM; apoptosis and reduced proliferation at 15 & 30 μM	Native form dissolved in DMSO; no enhanced delivery system used	5 μM showed cytostatic effect (senescence), while 15 & 30 μM led to cytotoxicity via apoptosis	[18]
Nanoparticles with curcumin and piperine modulate steroid biosynthesis in prostate cancer	2025	Prostate cancer cell lines (LNCaP, VCaP, DU145, PC3), adrenal NCI-H295R, normal RWPE-1	20 µM for 4 h and 24–48 h treatments	CYP17A1, CYP21A2, AR signaling, steroidogenesis	Inhibition of CYP17A1 (17α-hydroxylase & 17,20-lyase), reduced gene expression of CYP17A1, modulation of POR and CYB5A	↓ Viability, ↓ migration, ↑ S-phase arrest, selective cytotoxicity in cancer cells, ↓ androgen production	PLGA-based nanoparticles (CN, PN, CPN)	CPN >CN >curcumin; synergistic inhibition of steroidogenesis; enhanced bioavailability and cellular uptake; reduction in cortisol, testosterone, and androstenedione	[22]

The following abbreviations are used throughout Table 2. They are listed in alphabetical order for clarity:

Abbreviation: AKR1C2 Aldo-keto reductase family 1 member C2, AR Androgen Receptor, ATM Ataxia-telangiectasia mutated, Bax Bcl-2-associated X protein, Bcl-2 B-cell lymphoma 2, CD31 Cluster of Differentiation 31 (endothelial marker), CD44 Cluster of Differentiation 44, CDK Cyclin-dependent kinase, CYP17A1 Cytochrome P450 17A1, DHT Dihydrotestosterone, DR4/DR5 Death Receptor 4/5, EGFR Epidermal Growth Factor Receptor, EMT Epithelial–Mesenchymal Transition, FAK Focal Adhesion Kinase, HSD Hydroxysteroid dehydrogenase, ILK Integrin-Linked Kinase, LDHA Lactate Dehydrogenase A, MAPK Mitogen-Activated Protein Kinase, miR microRNA, MMP Matrix Metalloproteinase, mTOR Mammalian Target of Rapamycin, PARP Poly (ADP-ribose) Polymerase, PCa Prostate Cancer, PCLAF PCNA Clamp Associated Factor, PDHA1 Pyruvate Dehydrogenase E1 Alpha 1 Subunit, PI3K Phosphoinositide 3-Kinase, PLGA Poly (Lactic-co-Glycolic Acid), PSA Prostate-Specific Antigen, RIP3 Receptor-Interacting Protein Kinase 3, ROS Reactive Oxygen Species, SGK1 Serum/Glucocorticoid Regulated Kinase 1, STAT3 Signal Transducer and Activator of Transcription 3, TNF-α Tumor Necrosis Factor Alpha, ZEB1 Zinc Finger E-box Binding Homeobox 1

Molecular pathways targeted

Curcumin modulated several oncogenic and tumor-suppressor pathways, with a notable emphasis on the PI3K/Akt/mTOR axis, reported in eight studies. For instance, De Velasco et al. (2020) demonstrated that nanoparticle curcumin (Theracurmin®) effectively suppressed PI3K/Akt activation in a Pten-deficient mouse model, thereby reducing proliferation in early-stage prostate lesions [11]. Chen et al. (2020) further confirmed that curcumin co-delivered with cabazitaxel in aptamer-functionalized hybrid nanoparticles enhanced downregulation of PI3K/Akt and NF-κB signaling, resulting in marked tumor regression in vivo [12].

Similarly, NF-κB inhibition was reported in seven studies, often linked to reduced inflammatory signaling and apoptosis induction. Al-Rabia et al. (2022) showed that scorpion venom–conjugated phytosomes containing curcumin significantly downregulated NF-κB and TNF-α in PC3 cells, leading to enhanced apoptotic cell death [13].

Curcumin also interfered with androgen receptor (AR) signaling in six studies. The curcumin derivative H10 selectively inhibited 17β-HSD3 activity, thereby lowering testosterone production and suppressing AR-driven tumor progression [12]. Nakayama et al. (2021) reported that curcumin in combination with dutasteride synergistically reduced PSA secretion and AR expression in LNCaP cells [14].

In addition, apoptosis-related proteins (Bax, Bcl-2, caspases) were reported in 13 studies, consistently demonstrating activation of intrinsic and extrinsic cell death pathways. Some studies highlighted broader stress responses; for example, Lee et al. (2021) described dual activation of apoptosis and necroptosis in acidity-adapted PCa cells, mediated by oxidative stress and mitochondrial dysfunction [15].

Finally, modulation of epithelial–mesenchymal transition (EMT) regulators was documented in four studies. Bevacqua et al. (2021) found that dextran-curcumin nanosystems significantly downregulated ZEB1 and vimentin while upregulating E-cadherin, thus impairing migratory capacity of prostate cancer cells [16].

The frequency of targeted molecular pathways across included studies is illustrated in Fig. 2. Apoptosis-related proteins were the most frequently studied (13/22), followed by PI3K/Akt/mTOR (8/22), NF-κB (7/22), AR signaling (6/22), and EMT regulators (4/22).

Fig. 2.

Frequency of molecular pathways targeted by curcumin in prostate cancer studies

Therapeutic outcomes

Induction of apoptosis was the most consistent therapeutic effect, reported in 18 of the 22 studies. Mechanistic markers included Bax upregulation, caspase-3 activation, and PARP cleavage, frequently accompanied by Bcl-2 downregulation. For example, Pan et al. (2021) demonstrated that curcumin upregulated miR-30a-5p and consequently suppressed PCLAF, thereby triggering apoptosis in both PC-3 and DU145 cells as well as in patient-derived tissues [17].

In addition to apoptosis, cell cycle arrest was a recurrent finding. Ten studies described G1 or G2/M arrest, depending on the model and dose. Tossetta et al. (2025) reported a dose-dependent effect in 22Rv1 cells, where low doses induced a senescence-like state, while higher concentrations triggered apoptosis [18].

Suppression of migration and invasion was reported in 11 studies, often mediated through EMT regulation and integrin signaling. Rutz et al. (2021) showed that curcumin in combination with light irradiation reduced integrin expression and focal adhesion kinase activity, strongly limiting cell adhesion and metastatic potential [19].

Furthermore, curcumin inhibited angiogenesis in multiple in vivo models. Mapoung et al. (2020) observed reduced CD31 expression and decreased vascularization in xenograft tumors treated with dehydrozingerone, a curcumin analog [20].

Curcumin also demonstrated effects on cancer metabolism, with Pellegrino et al. (2024) reporting direct binding to PDHA1 and suppression of oxidative phosphorylation and lipogenesis, highlighting a role in metabolic reprogramming [21].

Delivery systems and nanoformulations

One of the major limitations of free curcumin is poor solubility and bioavailability. Several studies overcame this challenge through advanced delivery systems. Theracurmin® was shown to achieve more than 40-fold improved bioavailability, translating into reduced tumor proliferation in Pten-deficient mice [11]. Dextran-curcumin nanoparticles enhanced intracellular ROS production and blocked EMT [16]. Scorpion venom–conjugated phytosomes demonstrated superior induction of apoptosis and mitochondrial dysfunction compared to free curcumin [13]. Moreover, PLGA-based nanoparticles co-loaded with curcumin and piperine effectively inhibited steroid biosynthesis and androgen production, underscoring the therapeutic value of multifunctional nanocarriers [22].

A schematic overview of nanoformulation strategies, delivery improvements, and molecular mechanisms of curcumin in prostate cancer is presented in Fig. 3.

Fig. 3.

Schematic overview of curcumin nanoformulations, delivery strategies, and molecular mechanisms in prostate cancer. Nanoformulations such as liposomes, PLGA nanoparticles, Theracurmin®, dextran-curcumin, and phytosomes improve solubility, bioavailability, and tumor targeting. These improvements enhance curcumin uptake and action, leading to modulation of key molecular pathways including PI3K/Akt/mTOR, NF-κB, and androgen receptor signaling, as well as induction of apoptosis, inhibition of EMT, regulation of tumor-suppressive microRNAs, and suppression of angiogenesis

Combination therapies

Several studies explored combination strategies to enhance curcumin’s efficacy. Curcumin combined with chemotherapeutics (e.g., docetaxel, cisplatin, cabazitaxel) showed additive or synergistic effects, particularly in suppressing proliferation and promoting apoptosis (Chen et al., 2020; Boccellino et al., 2022) [12, 23]. Natural compounds such as quercetin and carnosic acid potentiated curcumin’s anticancer effects at lower concentrations, with mechanisms involving ROS generation, mitochondrial dysfunction, and modulation of NF-κB and MAPK pathways [24, 25]. Physical enhancers, particularly light irradiation, significantly amplified curcumin’s cytotoxicity at ultralow doses, suggesting applications in photodynamic therapy [19].

Discussion

Curcumin, a dietary polyphenol derived from Curcuma longa, has been extensively studied for its pleiotropic biological activities, particularly its anticancer potential. This systematic review provides compelling preclinical evidence supporting curcumin's multi-targeted effects in prostate cancer (PCa), acting through diverse molecular pathways, cellular mechanisms, and delivery strategies. The findings highlight both the therapeutic promise and translational challenges associated with curcumin-based interventions.

While numerous reviews have summarized the general anticancer properties of curcumin, our work is novel in that it systematically and exclusively focuses on prostate cancer, incorporating both molecular mechanisms and nanoformulation strategies. By applying rigorous quality assessment tools and including studies published up to March 2025, this review provides an updated and more clinically oriented perspective compared to earlier narrative or broad-spectrum reviews.

A prominent mechanism by which curcumin exerts antitumor activity is through inhibition of the PI3K/Akt/mTOR axis, a signaling hub critically involved in prostate tumorigenesis, particularly in PTEN-deficient contexts [11]. Notably, nanoparticle-formulated curcumin (Theracurmin) effectively downregulated PI3K/Akt signaling in early-stage PCa without inducing apoptosis, suggesting a chemopreventive rather than cytotoxic mode of action [11]. In contrast, functionalized hybrid nanoparticles co-delivering curcumin and cabazitaxel not only suppressed PI3K/Akt and NF-κB pathways but also synergistically enhanced apoptosis and tumor regression in vivo, demonstrating the power of rational combination therapy [12].

Curcumin's modulation of androgen receptor (AR) signaling further underpins its relevance in both hormone-sensitive and castration-resistant PCa. The curcumin analog H10 selectively inhibited 17β-HSD3 activity, reducing intratumoral testosterone levels without affecting upstream enzymes [27]. This targeted steroidogenesis inhibition translated to AR suppression and tumor growth reduction. Similarly, combined curcumin-dutasteride treatment significantly reduced PSA expression, induced DNA damage, and enhanced apoptosis, reinforcing curcumin's potential as an adjunct to androgen deprivation therapy [14].

Apoptosis induction was a consistent and potent effect observed across multiple models. Mechanistic studies revealed activation of intrinsic (Bax, caspase-3) and extrinsic (DR4/DR5) apoptotic pathways, often coupled with mitochondrial dysfunction and ROS generation [13, 15, 17]. Interestingly, in acidity-adapted PCa cells mimicking the tumor microenvironment, curcumin triggered both apoptosis and necroptosis—a rare and highly cytotoxic combination—via oxidative stress and ATP depletion, selectively killing cancer cells while sparing normal epithelium [15]. Such dual-mode cell death could offer a promising strategy to overcome resistance in advanced PCa.

Beyond cell death, curcumin inhibited migration, invasion, and angiogenesis by modulating EMT markers (e.g., E-cadherin↑, ZEB1↓, vimentin↓) and angiogenic regulators (CD31↓) [16, 20]. These effects are crucial in metastatic PCa models such as PC-3 and DU145, suggesting curcumin’s utility not only in tumor suppression but also in preventing disease progression.

However, curcumin's poor bioavailability remains a major translational barrier [9]. Several studies overcame this by employing nanoformulations—Theracurmin, dextran-curcumin systems, scorpion venom-conjugated phytosomes, and PLGA nanoparticles—each showing enhanced solubility, cellular uptake, and antitumor efficacy [11, 13, 16, 22]. Notably, PLGA nanoparticles co-loaded with curcumin and piperine inhibited steroid biosynthesis and androgen production in PCa cell lines more effectively than free curcumin [22]. Such delivery platforms not only improve pharmacokinetics but also enable lower dosing and targeted delivery.

The synergistic effects of curcumin in combination therapies are another major highlight. Co-administration with chemotherapeutics (e.g., docetaxel, cisplatin), natural compounds (e.g., quercetin, carnosic acid), or physical enhancers (e.g., light irradiation) consistently amplified its anticancer potency [19, 24, 25]. For instance, light-activated curcumin suppressed proliferation and integrin signaling at ultralow doses, with minimal toxicity, opening avenues for photodynamic interventions [19]. These findings emphasize that curcumin's full therapeutic potential may be realized when integrated into multimodal treatment regimens.

Mechanistically, curcumin's interaction with emerging molecular targets adds a novel dimension to its anticancer action. Several studies reported upregulation of tumor-suppressive microRNAs (miR-30a-5p, miR-383, miR-708), leading to inhibition of key oncogenic proteins like PCLAF, LDHA, and RAP1B [17, 31]. Other studies demonstrated copper-mediated redox cycling and oxidative DNA damage induced by curcumin in cancer cells, offering a mechanism of selective cytotoxicity not reliant on canonical apoptotic triggers [29]. Furthermore, modulation of energy and lipid metabolism through direct binding to PDHA1 and downregulation of lipogenic genes suggests a metabolic reprogramming role for curcumin in PCa [21].

While previous reviews have addressed the anticancer effects of curcumin in general oncology, few have provided a systematic and mechanistic synthesis focused specifically on prostate cancer. Furthermore, most earlier reviews lacked critical appraisal of study quality and did not comprehensively analyze advanced delivery systems. This review is distinct in integrating molecular mechanistic insights with nanoformulation strategies, offering a more translational perspective. The inclusion of recent studies (up to March 1, 2025) ensures that the findings are current and reflective of evolving research trends.

Figure 4 summarizes the principal molecular pathways modulated by curcumin in prostate cancer models, highlighting its inhibitory effects on oncogenic signaling, epigenetic regulators, and downstream hallmarks of cancer progression.

Fig. 4.

Mechanistic pathways targeted by curcumin in prostate cancer. Curcumin modulates multiple oncogenic signaling pathways—including PI3K/Akt/mTOR, NF-κB, androgen receptor (AR), and STAT3—leading to suppression of cell proliferation, induction of apoptosis and necroptosis, cell cycle arrest, and inhibition of migration and angiogenesis. Curcumin also regulates epigenetic mechanisms via miRNA modulation and EMT inhibition, contributing to reduced tumor aggressiveness and metastatic potential. This figure also serves as a graphical summary of the study, highlighting the dual focus on molecular mechanisms and nanoformulation strategies of curcumin in prostate cancer

Limitations and future directions

Despite the promising preclinical evidence, several limitations must be acknowledged. The heterogeneity of curcumin formulations, dosing regimens, and treatment durations across studies impedes direct comparison and prevents the definition of clear efficacy thresholds. Moreover, variability in experimental models—including differences between prostate cancer cell lines and diverse in vivo systems (e.g., xenograft vs. transgenic models)—further complicates the extrapolation of findings.

Another important consideration is the potential for publication bias. Studies reporting positive results are more likely to be published, which could lead to an overestimation of curcumin’s true therapeutic potential in prostate cancer models. A systematic effort to include unpublished negative or neutral data would provide a more balanced perspective.

Beyond issues of bioavailability, translational challenges associated with nanoformulations also warrant attention. These include the risk of unforeseen toxicity or immunogenic responses, difficulties in large-scale manufacturing, and batch-to-batch variability that can undermine reproducibility and regulatory approval. Such hurdles must be systematically addressed before curcumin nanoformulations can advance into late-stage clinical evaluation.

Future research should prioritize: (1) standardized dosing and formulation protocols; (2) pharmacokinetic and toxicological profiling in both animals and early-phase clinical studies; (3) biomarker-driven patient stratification for personalized curcumin-based therapy; and (4) exploration of curcumin as an adjuvant in immunotherapy and radiotherapy contexts.

Conclusion

This systematic review highlights the robust preclinical evidence supporting curcumin as a multifaceted anticancer agent in prostate cancer. By modulating key oncogenic pathways—including PI3K/Akt/mTOR, NF-κB, AR signaling, and epigenetic regulators—curcumin exerts potent anti-proliferative, pro-apoptotic, anti-metastatic, and anti-angiogenic effects across various cellular and animal models. Advanced delivery systems and synergistic combination therapies further enhance its bioactivity, providing a strong rationale for its integration into multimodal therapeutic strategies.

Despite these promising findings, curcumin’s clinical translation is hampered by pharmacokinetic limitations, lack of standardized formulations, and insufficient clinical validation. To bridge this gap, future studies must focus on well-designed pharmacological profiling, optimization of delivery platforms, and biomarker-based patient selection. Curcumin’s capacity to target multiple hallmarks of cancer with minimal toxicity positions it as a compelling candidate for adjunctive therapy in prostate cancer. Carefully designed clinical trials are warranted to evaluate its efficacy, safety, and therapeutic synergy in real-world settings.

Authors’ contributions

"All authors contributed to the conceptualization of this study. ME developed the study protocol. MD and ME compiled and organized the data. The initial draft of the manuscript was authored by ME and was thoroughly reviewed and revised by all the authors."

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Data availability

“All data analysed in this study were extracted from previously published articles, which are cited within the manuscript. No new datasets were generated.”

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing Interests

The authors declare no competing interests.