Therapeutic potentials of curcumin in prostate cancer: a comprehensive review of pathways and clinical prospects

Abstract

Prostate cancer (PCa), which occurs mainly in men over the age of 65, is the most common cancer and the second-leading cause of cancer-related death in men. Depending on the condition, approaches like radical prostatectomy, chemotherapy, radiotherapy, and androgen-deprivation therapy may be used to treat the patient. However, none of these treatment methods are sufficient to treat PCa. Hence, significant efforts have been made to improve the quality of PCa treatment, and curcumin has demonstrated great potential as an effective treatment. Curcumin, a polyphenol found in the rhizome of turmeric, has attracted significant attention due to its effects on numerous cancer-related biological pathways. This review provides an overview of the efficacy of curcumin against prostate cancer and includes in vivo, in vitro, and human studies. The findings of this study suggest that curcumin can enhance PCa treatment by regulating several cellular signaling pathways, including androgen receptor (AR), activator protein 1 (AP-1), nuclear factor kappa-B (NF-κB), Bcl-2 family, Wnt/β-catenin, phosphoinositide 3-kinases/Akt (PI3K/Akt), and orchestrating the expression of oncogenic microRNAs and tumor suppressor microRNAs. Furthermore, research indicates that curcumin sensitizes cancer cells to radiotherapy and chemotherapy. In conclusion, curcumin shows great promise in improving prostate cancer treatment by targeting key cancer pathways and enhancing the effects of existing therapies. While its potential is clear, further clinical studies are needed to refine its use and ensure its effectiveness in real-world applications.

1. Introduction

Conventional treatments for prostate cancer (PCa), one of the most common prevalent neoplasms in men, include surveillance, prostatectomy, radiotherapy, androgen ablation by surgical or pharmacological castration. These treatments can have side effects, including erectile dysfunction and urinary incontinence.^{1, 2, 3} One of the main risk factors for PCa is a reduction in testosterone levels. Testosterone plays a key role in the proper functioning of endothelial cells, particularly in the vascular endothelium, where it contributes to nitric oxide production—a potent vasodilator—that supports oxygen and nutrient delivery to tissues. This can consequently lead to several complications, including—but not limited to—cellular dysfunction, impaired regulatory mechanisms and homeostasis, prostate tissue remodeling or degeneration, and disruption of the protective role of p53 proteins in inflammation and their tumor-inhibiting functions.^4,5 PCa progression depends on the androgen receptor pathway and a metabolic change to the Warburg effect, which promotes lactate production over efficient energy production. This increased lactate formation is mainly for the rapid production of adenosine triphosphate (ATP) and the generation of precursors for biosynthetic pathways needed for the rapid division of cancer cells. Lipid biosynthesis and uptake are also increased in PCa for membrane and energy storage requirements, imparting tumor aggression in that regard. Upregulation of one-carbon metabolism (including folate and methionine cycles) provides nucleotide synthesis, epigenetic remodeling, and redox homeostasis in response to chronic tumor growth. The tumor microenvironment (TME) and cancer cells interact metabolically. This interaction creates a niche that potentiates neovascularization and tumor proliferation, leading to metastasis. The complex biology of PCa stems from metabolism, making it a promising target for natural treatments. In this regard, polyphenols, particularly curcumin, have revealed considerable therapeutic capacity.^{6, 7, 8, 9} Recently, curcumin and its related products have been shown to have potential effects on PCa.^{10, 11, 12, 13, 14} Curcumin, a polyphenol found in turmeric's rhizome, has anti-inflammatory, antioxidant, and antimicrobial properties, which have significant health benefits both in vivo and in vitro.^{15, 16, 17} The therapeutic effects of curcumin have been investigated in many diseases, including malignancies, mental problems, cardiovascular diseases, and metabolic disorders.^{18, 19, 20, 21, 22, 23, 24, 25, 26} It shows anticancer activities in cancer progression through different cellular and molecular mechanisms, such as inhibiting glucose absorption and lactate production, inducing apoptosis, and orchestrating involved signaling pathways (e.g. nuclear factor kappa-B [NF-κB] and JAK2/STAT3).^{27, 28, 29, 30} In the context of PCa, there are also promising reports highlighting its anticancer potential. For example, Tossetta et al. (2025) have shown that curcumin at low doses (5-30 μM) stimulates senescence-like impacts and hinders cell cycle arrest at the G2/M phase in PCa cells (22Rv1).³¹ Another recent study (2025) has indicated the synergistic effects of curcumin with ursolic acid in PCa in vivo and in vitro through the inhibition of oncogenic pathways (e.g. STAT3 and mTORC1) and regulation of cell regulatory proteins, leading to the repression of tumor cell proliferation.³² Hence, in this narrative review, we aimed to summarize and discuss the available recent advances regarding curcumin's role in improving PCa's prognosis as an adjuvant treatment, with a mechanistic insight into the involved cellular and molecular mechanisms.

2. Prostate cancer and recent treatment

According to the GLOBOCAN report of 2022, 1466680 new cases of PCa were diagnosed.³³ In some cases, including elderly patients whose life expectancy is less than 10 years or patients with low-grade tumors, treatment may not be required. Active surveillance is used for the remaining patients with low-risk PCa. Additionally, radiation therapy, radical prostatectomy, and cryotherapy are used for patients with moderate risk, which may have adverse effects such as urinary incontinence, Rectal pain, Urinary urgency and frequency, and erectile dysfunction. For more advanced tumors, androgen deprivation therapy (ADT), chemotherapy, and radiotherapy may be used, which can have adverse effects including peripheral neuropathy, myelosuppression, osteoporosis, insulin resistance, cognitive deficits, and hypersensitivity reactions.^{1,34, 35, 36}

Nanomedicine, as a promising therapeutic approach, offers the advantage of targeted drug delivery while minimizing adverse effects on surrounding tissues, such as toxicity. Additionally, it can encapsulate therapeutic agents, enhance their water solubility, prolong systemic circulation, and reduce premature clearance. Considering that very few nanotherapeutics have reached clinical trials, this underlines the critical need for well-thought-out nanotherapeutic design in the arena of PCa treatment.³⁷

The PCa exhibits exceptionally diverse molecular landscapes; several signaling pathways and genetic mutations affect disease progression and drug resistance. NEO2734, a novel dual inhibitor, has been developed against both bromodomain and extra-terminal (BET) proteins, including BRD4 and CBP/p300, which belong to a family of transcriptional coactivators with histone acetyltransferase activity. Hence, a newly developed therapeutic strategy targets the most frequently mutated gene in PCa, SPOP.^{38, 39, 40} Under normal conditions, wild-type SPOP plays a pivotal role in regulating cellular protein levels via binding and promoting the degradation of the BET proteins. However, the regulatory capacity is lost when Speckle-type pox virus and zinc finger (POZ) protein (SPOP) is mutated, leading to uncontrolled accumulation of BET proteins, thereby imparting a potential cancer growth advantage via triggering gene expression pathway deregulation. The resultant loss of function frequently confers drug resistance to BET inhibitors in SPOP-mutant PCa patients. Preclinical studies have revealed that NEO2734 effectively inhibits growth in SPOP-mutant PCa. Moreover, the results obtained with NEO2734 in enzalutamide-resistant PCa cells and patient-derived organoids suggest the potential application of this agent as an alternative means of treating cases resistant to antiandrogen treatments. Furthermore, recent investigations have also investigated the AR splice variants' (AR-Vs) role in the enhanced castration resistance in PCa. It was noted that NEO2734 antagonizes the mechanisms of antiandrogen-induced ferroptosis. This capability of NEO2734 represents a promising strategy for overcoming the resistance to currently available treatments. NEO2734 is currently under trial in Klinische Studien für PCa-Patients, NCT05488548. This trial will evaluate whether NEO2734 is safe, well tolerated, and highly active in about half of castration-resistant prostate cancer (CRPC) patients, thereby offering hope for a new therapeutic approach targeting multiple components of the complex molecular machinery that drives PCa progression.⁴¹

A novel therapeutic approach for CRPC is radioligand therapy (RLT) utilizing PSMA-targeted ligands labeled with Actinium-225 (225Ac) or Lutetium-177 (177Lu). Among these, 177Lu-PSMA RLT has demonstrated a more robust prostate-specific antigen (PSA) response and significantly fewer complications compared to cabazitaxel. Findings from the VISION trial support the clinical integration of 177Lu-PSMA RLT, showing that its combination with the standard of care yields superior efficacy compared to standard care alone. In contrast, 225Ac emits high-energy alpha particles that induce double-stranded DNA damage, offering potent tumoricidal activity. When used as a last-line treatment, 225Ac-PSMA RLT has shown potential for durable tumor control. The single-center design and small sample size characterize the main limitations. Therefore, a large multicenter trial needs to be conducted to confirm the safety and antitumor activity of Ac-PSMA RLT in metastatic CRPC.⁴²

However, despite the existing treatment methods, PCa is still incurable, and due to the low effectiveness and adverse effects of current treatments, there is a need for new and better treatments.

3. Effects of curcumin on prostate cancer

3.1. In-vitro

3.1.1. Androgen receptor

The androgen receptor is a ligand-activated transcription factor that plays an important role in PCa. When 5-alpha-dihydrotestosterone (DHT) or testosterone binds to the androgen receptor (AR), the AR is activated and translocated to the nucleus, where it regulates the expression of genes that induce cell proliferation and inhibit apoptosis. This pathway plays a key role in the growth and development of PCa, such that almost all PCa cells depend on AR signaling and androgens for growth (Fig. 1A).^{43, 44, 45, 46} Several studies have shown that curcumin can reduce androgen receptor gene expression and activity. For example, Guo et al. showed that it increases apoptosis and cell cycle arrest by increasing NF-kappaB inhibitor IkappaBalpha and decreasing AR and c-Jun levels.⁴⁷ Similarly, it can have therapeutic effects on LNCaP and PC-3 cells by reducing AR and AR-related cofactors (activator protein 1 [AP-1], NF-kappaB, and (CREB)-binding protein (CBP)) (Table 1).⁴⁸

Figure 1.

Molecular mechanisms of curcumin's effect on prostate cancer cells.

Abbreviations: apoptotic peptidase activating factor 1 (APAF1); activator protein 1 (AP-1); adenomatous polyposis coli (APC); androgen receptor (AR); Bcl-2 homologous antagonist killer/BCL2 associated X (Bak/Bax); casein kinase 1 alpha (CK-1α); c-Jun N-terminal kinase (JNK); endothelial nitric oxide synthase (eNOS); epidermal growth factor (EGF); epidermal growth factor receptor (EGFR); extracellular signal-regulated kinase (ERK); Fas-associated protein with death domain (FADD); G protein-coupled receptors (GPCR); glucose transporters type 1 and 4 (GLUT 1 and 4); glycogen synthase kinase 3 (GSK3); glycogen synthase kinase 3 beta (GSK-3β); heat shock protein (HSP); IkappaB kinase (IKK), apoptosis signal-regulating kinase 1 (ASK1); insulin receptor substrate (IRS); IκB kinase (IKK); lipoprotein receptor-related proteins 5 and 6 (LRP5/6); microRNA (miR); mTOR Complex 2 (mTORC2); nuclear factor kappa B (NF-κB); nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha (IκBα); octamer-binding transcription factor 4 (OCT4); phosphatase and tensin homolog (PTEN); phosphate (P); phosphatidylinositol 3,4,5-trisphosphate (PIP3); phosphatidylinositol 3-kinase (PI3K); phosphatidylinositol 4,5-bisphosphate (PIP2); programmed cell death 4 (PDCD4); pyruvate dehydrogenase kinase 1 (PDK1); receptor tyrosine kinases (RTK); SRY-Box transcription factor 2 (SOX2); TCF/LEF (T cell factor/lymphoid enhancer factor); testosterone (T), dihydrotestosterone (DHT); TNFRSF1A associated via death domain (TRADD); tuberous sclerosis proteins 1 and 2 (TSC1/TSC2); tumor necrosis factor (TNF); tumor necrosis factor receptor (TNFR).

Table 1.

The effects of curcumin on PCa in in-vitro studies.

Author/year	Type of cell/model	Intervention	Cell cycle arrest	Apoptosis	Proliferation	Cell Viability	Reference
Huandong Zhao et al. (2024)	LNCaP and PC3	LY2835219 (0.1 μM) + CUR (10 μM)	↑	-	↓	-	10
Reza Panahizadeh et al. (2023)	CD44- and CD44+	CD44- (0-70 μM CUR)/CD44+ (15-150 μM curcumin)	-	↑	-	-	73
Mohammad Amin Vatankhah et al. (2022)	CD44+	CUR + paclitaxel	-	↑	-	-	105
Liang Pan et al. (2021)	PC-3 and DU145	0, 10, 20, 30, 40, 50 μmol/l CUR	-	↑	↓	-	72
Jochen Rutz (2021)	DU145 and PC3	0.1-0.4 μg/mL CUR and 1.65 J/cm2 visible light for 5 min	↑	↑	↓	-	108
Seyed Sadegh Eslami et al. (2021)	LNCaP	15 μM CUR + 6 mM MET, 20 μM CUR + 4 mM MET, 20 μM CUR + 6 mM MET, 20 μM CUR + 8 mM MET, 25 μM CUR + 6 mM MET	-	↑	-	↓	104
Mingming Zhu et al. (2019)	22RV1, PC-3, and DU145	0, 0.1, 1, 5, 10, and 20 μmol/L CUR	-	-	↓	-	12
Shilpa Katta et al. (2019)	LNCaP and C4–2B	10 μM CUR	↑	↑	-	-	89
Te Liu et al. (2017)	HuPCaSCs	46.5 μM CUR	-	-	↓	-	75
Jianbo Liu et al. (2017)	PC3, DU145, and LNCaP cells	30 μM CUR + radiation (0.751 Gy/min)	-	↑	-	-	106
Jian Sha et al. (2016)	DU-145	25 mM CUR	↑	↑	↓	-	80

↓, decreased; ↑, increased; CUR, curcumin; EF24, diphenyl difluoroketone; LY2835219, LY CDK4/6 inhibitor; MET, metformin; PCa, prostate cancer.

3.1.2. Activator protein 1

The AP-1 is a transcription factor composed of various components, including the activating transcription factor (ATF) family, musculoaponeurotic fibrosarcoma (Maf) family, Jun-dimerizing partners (JDP), Fos family, and Jun family. Extracellular stimuli (e.g. interferons, oxidative stress, cytokines, and growth factors) and intracellular stimuli (e.g. mitogen-activated protein kinase [MAPK] and phosphoinositide 3-kinases [PI3K]/Akt signaling pathways) can activate AP-1. MAPK consists of three subfamilies, including p38, JNKs, and extracellular signal-regulated kinases (ERKs), which can activate AP-1. Once activated, AP-1 is translocated to the nucleus to regulate the transcription of target genes, including those involved in apoptosis, invasion, cell growth, drug resistance, metastasis, and angiogenesis (Fig. 1B).^{49, 50, 51} It has been proposed that curcumin can significantly inhibit AP-1 activity in DU145 cells by increasing their sensitivity to tumor necrosis factor (TNF).⁵² In addition, it can inhibit cell proliferation and induce apoptosis by inhibiting this pathway in PC-3 cells (Table 1).²⁹

3.1.3. Nuclear factor kappa-B

Another target of curcumin is NF-κB, a crucial regulator of inflammatory signaling and the immune system, comprising five members: p100/p52, p105/p50, c-Rel, RelB, and p65 (RelA).^53,54 When the cell is not stimulated, NF-κB cannot translocate to the nucleus due to its binding to IκBα, a member of the IκB protein family, and its translocation to the nucleus requires the degradation of IκBα, which is performed by the IκB kinase (IKK) complex, a large multicomponent protein kinase complex consisting of three subunits, including IKKγ, IKKβ, and IKKα. After activation, IKK phosphorylates IκBα, and the proteasome-dependent pathway degrades the phosphorylated IκBα. In the next step, the released NF-κB is transported to the nucleus to activate the target genes (Fig. 1C).^{54, 55, 56} Research shows that NF-κB activation is increased in many cancers, where it regulates various genes involved in metastasis, invasion, angiogenesis, cell proliferation, and apoptosis inhibition.^53,57 Overexpression of NF-κB also causes resistance to radiotherapy and chemotherapy.⁵⁸ In PCa, the NF-κB gene is upregulated by up to 2-fold.⁵⁹ Curcumin has been shown to prevent the translocation of NF-κB to the nucleus in PC-3 cells by inhibiting IKKβ, and by significantly inhibiting NF-κB, it can induce apoptosis and inhibit cell proliferation (Table 1).^29,60

3.1.4. Micro RNA

The micro RNAs (miRNAs) are small non-coding RNAs (ncRNAs) that participate in various physiological and pathological functions by inhibiting the translation and stability of messenger RNAs (mRNA) and by interacting with other ncRNAs.^61,62 The deregulated expression of miRNAs is associated with cancer.⁶³ For example, in PCa, the expression of miR-145, miR-34a, miR-30a-5p, miR-383, and miR-708, known as tumor suppressors, is reduced, whereas the expression of miR-141 and miR-21, known as an oncogene, is increased.^{64, 65, 66, 67, 68, 69, 70, 71} Curcumin has been shown to affect the expression of miRNAs. For instance, it can increase the expression of miR-30a-5p, thereby inhibiting the expression of the PCNA clamp-associated factor (PCLAF) and resulting in increased apoptosis and inhibition of cell proliferation, migration, and invasion.⁷² Additionally, Panahizadeh et al. reported the induction of miR-383 and miR-708 expression and the inhibition of LSD1, RAP1B, PRDX3, and LDHA genes after treatment, which induced apoptosis.⁷³ Another study reported increased expression of miR-34a, resulting in inhibition of the β-catenin/c-myc axis and proliferation after curcumin treatment.¹² EF24, an analog of curcumin, suppresses the expression of miR-21, increases the expression of PDCD4 and PTEN, and suppresses the expression of cyclin D1 and KI67.⁷⁴ This supplement can also increase the expression of miR-145 while inhibiting the expression of lncRNA-ROR and Oct4, thereby reducing proliferation and invasion (Table 1 and Fig. 1D).⁷⁵ Therefore, curcumin can positively affect PCa by increasing tumor suppressor miRNAs' expression and reducing oncogenic miRNAs' expression.

3.1.5. Bcl-2 family

The B-cell lymphoma-2 (Bcl-2) family plays an important role in apoptosis through the regulation of mitochondrial outer membrane permeabilization (MOMP) and is divided into three subfamilies: antiapoptotic (including Bcl-2, Bcl-XL, Bcl-W, Bcl-B (Bcl2L10), MCL-1L, MCL-1, BFL-1/A1, Bcl2L12), pore-forming executioners (including Bax, Bak, Bok), and BH3-only (including BIM, BID, Puma, Mule, BAD, Noxa, BIK./BLK, BMF, HRK/DP5, Beclin-1, Bcl-Rambo (Bcl2L13), Bcl-G (Bcl2L14), MCL-1S108, MCL-1ES).^{76, 77, 78} In cancer, antiapoptotic proteins of the Bcl-2 family are overexpressed, and proapoptotic proteins of the Bcl-2 family are underexpressed.⁷⁹ It has been reported that curcumin can inhibit the antiapoptotic protein Bcl-2 and activate caspase-3 and caspase-9.⁸⁰ In addition, it decreases the expression of Bcl-XL and increases the expression of BIM, BAK, Puma, and Noxa (Table 1 and Fig. 1E).⁸¹

3.1.6. Phosphoinositide 3-kinases/Akt

The PI3K is a subfamily of heterodimeric lipid kinases that can phosphorylate the 3′-OH group of phosphatidylinositol of the plasma membrane.⁸² It consists of two subunits: the regulatory subunit p85 and the catalytic subunit p110. Based on different substrate molecules and p110 subgroups, it is divided into three subclasses: Class I, Class II, and Class III.⁸³ PI3K can be activated by various stimuli, such as cytokines, growth factors, and hormones.⁸⁴ Once activated, PI3K mediates the phosphorylation of its lipid substrate phosphatidylinositol 4,5-bisphosphate (PIP2) into phosphatidylinositol^{3, 4, 5}-trisphosphate (PIP3).⁸⁵ PIP3 then recruits intracellular Akt and phosphoinositide-dependent protein kinase-1 (PDK1) to the cell membrane. Afterward, Akt is activated by the phosphorylation of Thr308 through the PDK1 and phosphorylation of Ser473 by the mechanistic target of rapamycin complex 2 (mTORC2).⁸⁶ Akt, also known as protein kinase B (PKB), belongs to the AGC kinase family, which exists in three structural isoforms: Akt1/PKBα (Akt1), Akt2/PKBβ (Akt2), and Akt3/PKBγ (Akt3).⁸⁷ Activated Akt enhances cell proliferation, growth, survival, glycolysis, and angiogenesis by influencing downstream substrates such as endothelial nitric oxide synthase (eNOS), glycogen synthase kinase 3α/β (GSK3α/GSK-3β), apoptosis signal-regulating kinase 1 (ASK1), glucose transporters type 1 and 4 (GLUT 1 and 4), and IkappaB kinase (IKK) (Fig. 1F).⁸⁸ Curcumin inhibits the PI3K/Akt (PKB)/mTOR pathway in LNCaP cells by promoting dephosphorylation of PIP3 via upregulation of phosphatase and tensin homolog (PTEN).⁸⁹ Additionally, it inhibits this pathway and reduces proliferation in PC-3 cells by dephosphorylating calyculin A-sensitive proteins (Table 1).⁹⁰ Accordingly, curcumin as a PI3K/Akt pathway inhibitor could be a potential treatment accelerator for PCa.

3.1.7. Wnt/β-catenin

The Wnt/β-catenin, or the canonical Wnt signaling pathway, plays a vital role in many physiological processes, including differentiation, proliferation, apoptosis, invasion, migration, and tissue homeostasis. The main components of this pathway include T cell factor/lymphoid enhancer factor (TCF/LEF), Dishevelled protein (Dvl), receptors LRP5/6 and FZD (Frizzled), β-catenin, Wnt family proteins, and the β-catenin destruction complex, including casein kinase 1α (CK1α), glycogen synthase kinase-3β (GSK-3β), axin, and adenomatous polyposis coli (APC).⁹¹ When a Wnt ligand is present, Wnt binds to FZD and LRP5 or LRP6, which activates axin and Dvl, inducing phosphorylation of LRP5/6 and disrupting the β-catenin destruction complex. This process leads to the accumulation of unphosphorylated β-catenin in the cytoplasm, its translocation to the nucleus, and its interaction with TCF/LEF to activate transcription of Wnt target genes (Fig. 1G).^92,93 Studies have shown that disruption of this pathway significantly contributes to tumor progression as aberrant activation of this pathway has been observed in many types of cancers, such as prostate, colorectal, breast, cervical, gastric, and lung cancer.^{91,94, 95, 96, 97, 98, 99, 100} In PCa, aberrant activation of the Wnt signaling pathway can cause drug resistance and progression to CRPC.¹⁰¹ Curcumin reduces Wnt/β-catenin/Tcf-4 transcriptional activity in 22Rv1 cells but shows no efficacy in PC-3 cells.¹⁰² Furthermore, it decreases β-catenin accumulation by inhibiting GSK-3β phosphorylation, thereby suppressing the Wnt/β-catenin signaling pathway (Table 1).¹⁰³

3.1.8. Combination therapy

Curcumin, in combination with other treatments, may enhance their anticancer effects; hence, some studies have examined the impacts of combining this supplement with other treatments for PCa. For example, Eslami et al. examined the effectt of this supplement in combination with metformin on LNCaP cells. They observed that the combination of curcumin and metformin caused maximum levels of Bax gene expression, cytotoxicity, and apoptosis.¹⁰⁴ It has also been indicated that curcumin can reduce the chemoresistance of CD44⁺ cells to paclitaxel, increase the level of miR-148a, and reduce the expression of CD44⁺ and P-gp.¹⁰⁵ Moreover, curcumin sensitizes PC3, DU145, and LNCaP cells to radiation by restoring miR-143 and miR-145.¹⁰⁶ Similarly, another study showed that curcumin can sensitize PC3 and LNCaP cells to radiotherapy, and the combination of the two has synergistic effects on clonogenic cell death and inhibition of cell proliferation.¹⁰⁷ In examining the effect of visible light irradiation on the anticancer potential of curcumin, it was found that the combination significantly suppressed tumor adhesion, growth, and migration by decreasing Integrin α and β, cyclin A and B, and phosphorylation of CDK1 in PCa cells (Table 1).¹⁰⁸ Fig. 2 displays the effects of curcumin in combination with other treatments on PCa cells. Curcumin's anticancer potential is well documented in combination therapies targeting key signaling pathways. Building on this, recent studies have highlight synergistic effects when curcumin is paired with traditional Chinese medicinal herbs such as Sparganii Rhizoma, Rehmanniae Radix Praeparata, Psoraleae Fructus, and Sophorae Flavescentis Radix to combat PCa. These combinations modulate critical pathways, including Wnt/β-catenin, epidermal growth factor receptor (EGFR), AR, and PI3K/Akt/mTOR, demonstrating enhanced therapeutic efficacy compared to monotherapy approaches.¹⁰⁹ Further studies are needed to determine the effects of curcumin in combination with other drugs and treatments on PCa.

Figure 2.

The effects of curcumin in combination with other treatments on prostate cancer cells.

Abbreviations: aldehyde dehydrogenase 1 damily member A1 (ALDH1A1); autophagy related 2B (ATG2B); B-cell lymphoma 2 (Bcl-2); BCL2 associated X (Bax); cyclin-dependent kinase 1 (CDK1); DNA methyltransferase 3B (DNMT3B); DNA methyltransferase 1 (DMNT1); growth arrest and DNA damage (GADD45); human telomerase reverse transcriptase (HTERT); microRNA (miR); mechanistic target of rapamycin kinase (mTOR); p53 upregulated modulator of apoptosis (PUMA); phagocytic glycoprotein (P-gp); phospho-cyclin dependent kinase 1 (PCDK1); poly (ADP-ribose) polymerase (PARP); retinoblastoma protein (Rb); signal transducer and activator of transcription 3 (STAT3).

3.2. In vivo

The effect of curcumin on PCa has been investigated in several animal models. For example, Velasco et al. investigated the effectiveness of curcumin nanoparticles in theracurmin (a nanoparticle formulation of curcumin) in PTEN-deficient prostate cancer mice. After 16 weeks of receiving 76 mg/kg/day or 380 mg/kg/day of theracurmin, it was found that the cell proliferation of cancer cells decreased in the mice that received the high dose of theracurmin.¹¹⁰ Yallapu et al. investigated the therapeutic potential of poly(lactic-co-glycolic acid) CUR nanoparticles (PLGA-CUR NPs) for treating PCa. After one week of treatment, a decrease in tumor volume, growth inhibition of miR-125 expression, and an increase in miR-205 expression were observed.¹¹¹ In a study investigating its effectiveness on the androgen-dependent LNCaP prostate cancer model was investigated. After receiving 500 mg/kg curcumin three times weekly for 4 weeks, AR activity was inhibited, PSA expression was reduced, and tumor growth was delayed by 27%.¹¹² Yang et al. investigated the effects of this supplement on BALB/c nude mice. After 30 days of receiving 100, 50, and 25 mg/kg of curcumin, cancer cell growth was inhibited, tumor weight and volume decreased, and by reducing the expression of Bcl-2 and up-regulating Bax, it increased apoptosis.¹¹³ In another study, the epigenetic effect of this supplement was investigated in the treatment of PCa, tumor growth was inhibited after receiving 30 mg/kg of curcumin ¹¹⁴. Dorai et al. inspected the therapeutic potential of a diet containing 2% curcumin on this neoplasm. The results of this study showed that it can effectively reduce tumor growth, decrease cell proliferation, increase apoptosis, and decrease angiogenesis.¹¹⁵ In addition, Cheng et al. showed that after 14 days of treatment with H10, a curcumin analog, tumor growth, and 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3) enzyme activity were inhibited, and testosterone production was reduced.¹¹⁶ Chen et al. demonstrated that this supplement can downregulate the IGF-1/PI3K/Akt signaling pathway, increase apoptosis, and inhibit tumor growth.¹¹⁷ Another study indicated that 14 days of curcumin administration in C57BL/6 mice could reduce tumor weight and all immunological indices except the CD4⁺/CD8⁺ ratio¹¹⁸ (Table 2). More studies are needed to confirm these results and determine the appropriate dose.

Table 2.

The effects of curcumin on PCa in in vivo studies.

Author/Year	Experimental animal model	Intervention	Human equivalent doses	Outcome	Reference
Chao Chen et al. (2025)	BALB/c nude mice	100 mg/kg CUR	8.1 mg/kg CUR	Repressing tumor growth and stimulating apoptosis	117
Marco A De Velasco et al. (2020)	Pten-deficient mouse model	18600 mg/kg or 26600 mg/kg nanoparticle CUR	1506.6 mg/kg or 2154.6 mg/kg nanoparticle CUR	Attenuating cell proliferation	110
Yating Cheng et al. (2020)	Sprague-Dawley (SD) rats and nude mice	10 mg/kg, 30 mg/kg, or 50 mg/kg H10	0.8 mg/kg, 2.4 mg/kg, or 4 mg/kg H10	Reducing tumor growth, testosterone production, and inhibiting the 17β-HSD3 enzyme	116
Jing-Lei Mao et al. (2019)	C57BL/6 mice	50 mg/kg, 100 mg/kg, or 200 mg/kg CUR	4 mg/kg, 8.1 mg/kg, 16.2 mg/kg CUR	Decreasing tumor weight and all immunological indices except the CD4+/CD8+ ratio	118
Wanli Zhao et al. (2018)	Mouse	30 mg/kg CUR	2.4 mg/kg CUR	Repressing tumor growth	11
Jeong Hee Hong et al. (2015)	BALB/c nude mice	500 mg/kg CUR	40.5 mg/kg CUR	Inhibiting AR activity and decreasing PSA levels and tumor growth	112
Jiayi Yang et al. (2015)	Nude mice	25 mg/kg, 50 mg/kg, and 100 mg/kg CUR	2 mg/kg, 4 mg/kg, or 8.1 mg/kg CUR	Reducing tumor volume, weight, and growth and inducing apoptosis	113
Murali M. Yallapu et al. (2014)	Mice	2.5 mg/kg CUR	0.2 mg/kg CUR	Reducing tumor volume and cancer growth	111
T Dorai et al. (2001)	Nude mice	An experimental diet containing 2 % CUR	-	Reducing cell proliferation and angiogenesis, and inducing apoptosis	115

17β-HSD3, 17β-Hydroxysteroid dehydrogenase 3; AR, androgen receptor; CUR, curcumin; PCa, prostate cancer; PLGA-CUR NPs, lactic-co-glycolic acid-curcumin nanoparticles; PSA, prostate-specific antigen.

3.3. Human studies

Some studies have examined the effect of curcumin on patients with PCa and have finally published conflicting results. A majority of the current clinical studies emphasize the promising outlook of this therapeutic strategy for PCa cases. Regarding this matter, A pilot study (phase II) conducted by Mahammedi et al. investigated the efficacy of docetaxel/prednisone combined with oral curcumin (6,000 mg/day for 7 days) in 30 chemotherapy-naïve patients with metastatic CRPC. This clinical project reported a PSA response in 59% of patients, with 40% achieving a partial response. This curative regimen was well tolerated with no adverse effects related to curcumin and had high compliance among the patients.¹¹⁹ Another study assessed the efficacy of oral nanocurcumin (120 mg/day) versus placebo in 64 patients with prostate cancer undergoing radiotherapy. The research pointed out that nanocurcumin was well tolerated, with no considerable differences between the nanocurcumin and placebo groups in the incidence of radiation-caused proctitis, hematologic nadirs, duration of toxicities, cystitis, or tumor response.¹²⁰ The results of the study by Hejazi et al. showed that the prescription of curcumin supplementation (3 g/day) reduces superoxide dismutase (SOD) activity and increases total antioxidant capacity (TAC) compared to both baseline levels and the placebo group in patients with PCa undergoing radiotherapy. Also, PSA levels were effectively decreased in both the curcumin and placebo groups; however, no significant differences in treatment outcomes were observed between the two groups. Curcumin scavenges radiation-conferred free radicals directly, decreasing the need of the human body to produce its own antioxidant enzyme SOD. This phenomenon leads to a reduction in SOD levels. Concurrently, curcumin itself potentiates the blood's total antioxidant capacity. Substantially, the body shifts from using its own enzymatic capacity to relying on curcumin for protection, without reducing the effectiveness of radiotherapy.¹²¹ In addition, Choi et al. investigated the effect of curcumin in PCa patients with intermittent androgen deprivation (IAD) in a study. This study indicated that six months of curcumin therapy (1440 mg/day orally) suppressed PSA increases and reduced the side effects of IAD treatment but had no significant impact on the duration of IAD, testosterone levels or health-related quality of life (HRQOL) scores.¹²² Currently, in the recruitment stage, two phase 3 studies by Lotan et al. at the University of Texas Southwestern Medical Center will examine the effect of curcumin on cancer progression in patients undergoing active surveillance and improve recurrence-free survival after radical prostatectomy, with results yet to be published^123,124 (Table 3). Recently, a phase 1 clinical trial scrutinized the safety, bioavailability, and the influence of a combination of two natural compounds—curcumin and ursolic acid—formulated in a lipid-based formulation in healthy male volunteers, who were allocated into three groups, including the curcumin (n = 6, 1200 mg/day), ursolic acid (n = 6, 300 mg/day), and the combination (n = 6, 300 mg ursolic acid+ 1200 mg curcumin/day) groups. This human project revealed that curcumin at the mentioned dose is safe, with minor side effects; however, its bioavailability was negligible. Also, the combination therapy could significantly diminish a microbiome risk score related to prostate cancer.¹²⁵ In contrast to the positive results aforementioned for curcumin remedy in PCa subjects, a multicenter, randomized, clinical trial showed that the administration of high-dose curcumin (6 g/day for 7 days every 3 weeks) orally in combination with docetaxel as a standard chemotherapy did not improve progression-free survival, overall survival, and quality of life in cases with metastatic castration-resistant prostate cancer (mCRPC) compared to the placebo group. The authors declared that these negative outcomes are mainly due to the poor bioavailability of curcumin, because the active form was not detected in the bloodstream despite affirmed absorption of its metabolites.¹²⁶ These results suggest that further clinical trials with a larger sample size are needed to confirm the curative effectiveness of curcumin alone or in combination with other therapies in PCa patients. Moreover, further pharmacological investigations are needed to determine the effective and safe dose of curcumin in subjects with this malignancy.

Table 3.

The effects of curcumin on PCa in human studies.

Author/Year	Simple Size	Intervention	Outcome	Reference
Judith Passildas-Jahanmohan et al. (2021)	50	Docetaxel at 75 mg/m2 every 3 weeks for 6 cycles + 6 g/day of CUR	Lack of a considerable effect on the quality of life and overall survival	126
Young Hyo Choi et al. (2019)	97	1440 mg/day CUR	Suppressing PSA elevation and decreasing the side effects of IAD	122
Afshin Saadipoor et al. (2019)	64	RT + 120 mg/day nanocurcumin	Lack of significant differences in treatment efficacy or toxicity	120
Hakim Mahammedi et al. (2016)	26	75 mg/m2 docetaxel + 10 mg prednisone or Prednisolone + 6,000 mg/day CUR	Elevating the rates of tolerance, acceptance, and response to treatment	119
Jalal Hejazi et al. (2016)	40	3 g CUR + RT	Elevating TAC and decreasing SOD activity	121
Yair Lotan et al.	608	1 g CUR	Active and ongoing	123
Yair Lotan et al.	291	500 mg CUR	Active and ongoing	124

CUR, curcumin; HRQoL, health-related quality of life scores; IAD, intermittent androgen deprivation; PCa, prostate cancer; PSA, prostate specific antigen; SOD, superoxide dismutase; TAC, total antioxidant capacity.

4. Patents and products

The importance of curcumin in treating PCa is such that numerous new and combination products have been developed and patented. These products are usually formulated with a focus on increasing the bioavailability and anticancer activity of curcumin. One of these products, produced by Defeng et al., is a polymeric micelle loaded with dimethyl-curcumin. The polymeric micelle in this product increases the aqueous solubility and stability of dimethyl curcumin and enhances the killing effect of dimethyl curcumin on PCa cells.¹²⁷ Capsures is a combination of resveratrol and curcumin that causes a significant reduction in PSA.¹²⁸ Curcumin derivative Ca 37 (1,5-bis (3-hydroxyphenyl) −1,4-pentadien-3-one) exhibits superior antiproliferative effects, reduced oxidative phosphorylation, decreased cell growth and glycolysis, and induced apoptosis and autophagy defects compared to curcumin.¹²⁹ Another product is a derivative of curcumin that was produced by changing the substituents on the benzene ring and the β-diketone species in the curcumin structure. In these derivatives, R1 (HSO2CH3) and R3 (NHSO2CH3) exhibited greater AR inhibitory activity than dimethyl curcumin.¹³⁰ Curcumin analogs featuring a novel scaffold with basic heteroaromatic side groups demonstrate greater cell viability and growth inhibition than curcumin, with an IC50 at least 1.9-fold and up to 48-fold higher than that of curcumin in PC-3 cells, and an IC50 at least 1.2-fold and up to 30-fold higher than curcumin in DU145 cells.¹³¹ Targeted drug delivery systems combining nano-silver with curcumin or a curcumin derivatives, including hexahydrocurcumin, tetrahydrocurcumin, dihydrocurcumin, bis-demethoxycurcumin, and demethoxycurcumin can increase the bioavailability and solubility of curcumin and its derivatives and enhance their anticancer effects.¹³² Another derivative of curcumin was produced by changing the structure of the benzene ring or β-diketone of curcumin. The most potent, 4-benzyl-1,7-bis(3,4-dimethoxyphenyl)-5-hydroxyhept-1,4,6-trien-3-one, showed a lower IC50 (0.8922 μM) than dimethyl curcumin (1.07 μM) and stronger antiproliferative effects in 22Rv1 cells.¹³³ These derivatives represent a promising strategy to address the limitations of curcumin, though further validation through clinical trials remains essential to confirm their translational potential.

5. Curcumin’s medicinal limitations

Despite the benefits of curcumin in advancing cancer therapy, its clinical use has been limited due to its low solubility, low chemical stability, rapid metabolism, and poor bioavailability.^134,135 During absorption, curcumin is inefficiently transported across the intestinal epithelium and rapidly metabolized.¹³⁶ In addition, due to its hydrophobic nature, cellular uptake is limited.¹³⁵ For example, with the administration of 500 mg/kg curcumin in rats, a maximum serum concentration of 0.06 ± 0.01 μg/mL was observed, and its oral bioavailability was reported to be about 1%.¹³⁷ Many efforts have been made to increase curcumin's bioavailability, address its related challenges, and enhance its anticancer effects. One way to increase the bioavailability of curcumin is to combine it with piperine, an alkaloid extracted from the seeds of the Piperaceae family, which has antioxidant and anti-inflammatory activities.¹³⁸ The combination of these two can increase the bioavailability of curcumin by inhibiting the glucuronidase enzyme in the liver and intestines, with one study reporting a 2000% increase in its bioavailability.^138,139 Structural modifications of curcumin are another way to overcome its limitations. These modifications include hydrogenation of the alkene chain, changes in the β-diketone structure, modification of the benzene ring side chain, substitution of the methylene group, and hybrid and mixed modifications, which are combinations of the previous modifications.¹³⁵ 1, 2-bis [(3E, 5E)-3, 5-bis [(2-chlorophenyl) methylene]-4-oxo-1-piperidyl] ethane-1, 2-dione (ST03) is a curcumin derivative that has 14-fold greater bioavailability than curcumin and remains in plasma for more than 12 hours.¹⁴⁰ Curcumin nanoformulations, such as polymer NPs, phospholipid complexes, nanogels, nanofibers, nanocrystal conjugates, etc., can improve the solubility of curcumin and increase its bioavailability.¹⁴¹ For example, nanoliposomes containing curcumin and tetrandrine significantly increase the stability, solubility, and safety of the two.¹⁴² Niosomes are composed of nonionic surfactants and cholesterol from closed bilayer vesicles that can encapsulate hydrophilic drugs in their aqueous phase interior and lipophilic drugs in their lipophilic membrane. Encapsulating curcumin using them can improve the stability of curcumin.¹⁴³ These findings promise to address the challenges limiting curcumin’s beneficial health potential.

6. Conclusion

This literature review highlights that curcumin can effectively target PCa by reducing cancer proliferation, cell viability, tumor volume, and tumor weight, and increasing apoptosis and cell cycle arrest by inhibiting several pathways, including AR, AP-1, NF-κB, Wnt/β-catenin, modulating Bcl-2, regulating the expression of tumor-affecting microRNAs, and sensitizing cancer cells to radiotherapy and chemotherapy. However, there are some limitations in the current evidence, especially in clinical trials, such as a lack of large-scale, meticulous clinical trials, a lack of a unique standard formulation, and uncertainties in introducing the optimal effective dose for anticancer purposes, particularly in PCa cases. Also, heterogeneity in the population of assessed patients and insufficient attention to the different stages and grades of prostate cancer in these current studies make it difficult to address which groups may benefit the most from this therapeutic strategy. Furthermore, a few human studies have claimed that this polyphenol did not remarkably improve treatment outcomes once combined with other strategies like docetaxel or radiotherapy. Another point regarding curcumin therapy is related to its pharmacokinetics, considering its poor oral bioavailability, low water solubility, and rapid systemic elimination. Fortunately, novel formulations and alternative strategies have been suggested to conquer these pharmacological problems and improve the therapeutic effectiveness of curcumin, such as harnessing nano-based formulations (e.g. PLGA-CUR NPs, nanoliposomes, polymer NPs, and polymeric micelles), potential synergistic combinations with some natural compounds (ursolic acid, piperine, and resveratrol), and approaches like visible light irradiation in experimental studies, whose functionality can be evaluated in clinical investigations. Ergo, further preclinical and clinical attempts on this supplement are necessary to better understand its effects on prostate cancer prognosis.

Author contributions

M.R.F, F.S, M.A.M, H.D, and H.A contributed to the acquisition, analysis, and interpretation of data for the work. M.R.F and M.A.M contributed to the write-up of the review article. R.A and F.R.T: Contributed to the supervision, editing and designed the framework of the manuscript. P.N: editing. All authors read and approved the final version of the manuscript.

Informed consent

Not applicable.

Ethics approval

Ethical issues (including plagiarism, data fabrication, double publication) have been completely observed by the authors.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Funding

This work was not financially supported.

Conflicts of interest

The authors declare no competing interests.