Curcumin as a therapeutic agent in liver cancer: a systematic review of preclinical models and mechanisms

Abstract

Background

Curcumin, a bioactive compound derived from Curcuma longa, has gained attention for its potential therapeutic effects in liver cancer. We reviewed current literature to evaluate the efficacy of curcumin in liver cancer models, such as anti-proliferative, pro-apoptotic, anti-inflammatory, or anti-metastatic roles. This systematic review focused on experimental methods, dosages, and underlying mechanisms.

Methods

A comprehensive literature search was conducted across PubMed, Web of Science, Embase, and Google Scholar until December 2024. Inclusion criteria were studies using in vivo or in vitro models to assess curcumin's effects on liver cancer, with comparisons to control groups. A total of 26 studies (8 in vivo, 14 in vitro, 4 combined) were included. Data on curcumin administration methods, dosages, and outcomes were extracted. Study quality was assessed using a six-item scale. Descriptive statistics were used for data analysis with SPSS (Version 22.0).

Results

From the initial 1048 studies retrieved, 27 met the inclusion criteria. In vivo studies were conducted on various animals strains (C3H/HeN mice, Wistar rats, B6C3F1 mice, BALB/c nude mice and C57BL/6 mice). Curcumin was administered via oral (8 studies), intraperitoneal (2 studies), intragastric (1 study) and intravenous (1 study) routes, with 8 studies incorporating a dose gradient. The majority of studies used chemically-induced models, including N-diethylnitrosamine (DEN) and nitrosodiethylamine (NDEA) models, as well as subcutaneous injections of liver cancer cell lines (HepG2, Bel7402). The included studies employed various techniques, including Western blotting, RT-PCR, flow cytometry, and migration assays. Curcumin significantly induced apoptosis in liver cancer cells, with 14 studies reporting dose-dependent increases in apoptosis markers such as caspase-3 and Bax expression. Anti-inflammatory effects were evident in 5 studies, with curcumin inhibiting NF-κB activation, a key pathway in liver cancer progression. Additionally, antioxidant and anti-angiogenic properties were observed, as curcumin reduced lipid peroxidation and decreased VEGF expression. Two studies highlighted curcumin’s potential in suppressing metastasis, with dose-dependent inhibition of liver cancer cell migration and invasion. The quality of included studies varied, with 21 out of 27 studies employing random allocation and 8 using blinded outcome assessments.

Conclusions

Curcumin demonstrates promising anti-cancer effects, including apoptosis induction, inflammation modulation, and metastasis inhibition. However, variability in study designs and lack of clinical trials necessitate standardized protocols and further clinical investigations to confirm its therapeutic potential in liver cancer treatment.

Introduction

Liver cancer is the sixth most common malignancy globally (865,269 new cases in 2022) and the thrid leading cause of cancer-related mortality (757,948 deaths in 2022), with a particularly high incidence and mortality rate in Asia [1]. Hepatocellular carcinoma (HCC) is the predominant form of primary liver cancer, with increasing incidence and poor prognosis despite advancements in early detection and treatment options [2]. The most common etiology of liver cancer is infection with the hepatitis B virus, although other risk factors, such as alcoholic steatohepatitis, nonalcoholic fatty liver disease, aflatoxin exposure from diet, smoking, and diabetes, also contribute to disease development [3]. In recent years, delayed diagnosis and the lack of effective therapies have resulted in high mortality and poor prognosis, with 841,080 clinically diagnosed cases and 781,631 deaths reported last year [4, 5].

Liver cancer treatments can be divided into locoregional therapies and systemic therapies. Locoregional therapies include: Liver transplantation, surgical resection, transcatheter arterial chemoembolization (TACE) and radiofrequency ablation (RFA) have been employed in the management of liver cancer [6, 7]. Systemic Therapies encompass conventional chemotherapy and radiotherapy, targeted therapy, and immunotherapy.

Locoregional therapies

Tumor resection and liver transplantation are generally applicable to patients with early-stage HCC. For patients who are not suitable candidates for surgery, RFA serves as a potential alternative. RFA is contraindicated when tumors are located near major blood vessels, bile ducts, or other critical abdominal organs due to the associated risk [8]. For patients with intermediate-stage disease, where the tumor is confined to the liver, TACE has shown effectiveness in controlling disease progression and providing survival benefits [9–11].

Systemic therapies

Unfortunately, cases of liver cancer are diagnosed at advanced stages, necessitating systemic therapy. The current first-line targeted therapies for advanced liver cancer include sorafenib, a tyrosine kinase inhibitor, and agents targeting the vascular endothelial growth factor (VEGF) receptor [12]. Although immunotherapy has demonstrated promising therapeutic effects, overall survival (OS) for advanced liver cancer has improved only marginally [13]. Despite these advances, current treatments are limited by severe side effects, such as appetite loss, diminished physical and role function, a high risk of hemorrhage, and significant treatment costs [14, 15]. Therefore, despite progress in medical technology, there remains a pressing need to develop safer and more effective treatment options, particularly chemopreventive agents, to reduce the incidence and mortality of liver cancer (Fig. 1).

Fig. 1.

Risk factors and treatments for liver cancer. The major risk factors for liver cancer (e.g., hepatitis, alcohol use, diabetes) and treatment options, including surgery, TACE, RFA, sorafenib, and immunotherapy

Alternative therapeutic strategies, including the use of natural compounds such as crocin, cranberry phenolic extract, gallic acid, modified citrus pectin, Withania somnifera L. Dunal extract, have started to receive increasing attention in recent years [16–20]. Curcumin, one of the most extensively studied natural compounds, is a yellow polyphenolic phytochemical native to Southeast Asia extracted from the rhizomes of Curcuma longa [21]. For over 40 centuries, curcumin has been utilized in traditional medicine to treat a variety of common ailments, including inflammation of the stomach, liver, and kidneys [22]. Curcumin has demonstrated a broad spectrum of biological activities, including anti-inflammatory, antioxidant, and anti-cancer effects [23]. Several studies have shown that curcumin exerts its anti-cancer effects through multiple molecular mechanisms, including the modulation of apoptosis, cell cycle regulation, and inhibition of key signaling pathways involved in cancer progression, such as Nuclear factor kappa-B (NF-κB), Signal transducer and activator of transcription 3(STAT3), and Mitogen-activated protein kinase (MAPK) [24, 25]. Recent preclinical studies have further supported curcumin's therapeutic potential against liver cancer, with promising results obtained from both in vivo and in vitro models. These studies suggest that curcumin can induce apoptosis, inhibit cell proliferation, and reduce the metastatic potential of liver cancer cells. Furthermore, curcumin has been shown to enhance the efficacy of conventional therapies, offering a promising adjunctive treatment in liver cancer management.

Given the growing interest in curcumin as a potential therapeutic agent for liver cancer, a comprehensive review of the existing literature is warranted to synthesize current findings and assess the overall effectiveness of curcumin in liver cancer models. This review aims to comprehensively evaluate current literature, focusing on the experimental models employed, dosages and methods of curcumin administration, and the mechanisms underlying its protective effects against liver cancer to obtain an overview of the current state of research, which could contribute to the development of more effective therapeutic strategies incorporating curcumin for the treatment of liver cancer.

Materials and methods

Search strategy

A comprehensive literature search was performed by two independent researchers to identify studies evaluating the effects of curcumin on liver cancer. The search was conducted from the inception of the databases until December 2024. Four electronic databases were queried: PubMed, Web of Science (WOS), Embase, and Google Scholar.

In PubMed/WOS/Embase, the search terms employed included a combination of Medical Subject Headings (MeSH) and keywords to capture relevant studies, as detailed below:

1. "Carcinoma, Hepatocellular"[Mesh] OR"Liver Neoplasms"[Mesh]

2. "liver"[Title/Abstract] OR"hepatic"[Title/Abstract] OR"hepatocellular"[Title/Abstract] OR"hepato-cellular"[Title/Abstract] AND"carcinoma*"[Title/Abstract] OR"cancer*"[Title/Abstract] OR"neoplasm*"[Title/Abstract] OR"malign*"[Title/Abstract] OR"tumor*"[Title/Abstract]

3. Combination of terms from 1 and 2

4. "curcumin"[Mesh] OR"Turmeric"[Title/Abstract] OR"Curcumin analogue"[Title/Abstract] OR"Curcu*"[Title/Abstract]

5. Combination of terms from 3 and 4

Records were extracted using Publish or Perish (version 8.12.4612), with the following detail: “intitle:("liver cancer"AND ("curcumin"))”. Google Scholar searches were screened by relevance order. The top 300 results were reviewed, covering approximately 30 pages until new relevant entries fell below 5%.

Study inclusion and exclusion

Studies included in this review were required to meet the following criteria: (1) studies that examined the effects of curcumin on liver cancer using either in vivo or in vitro models; (2) there were no restrictions on publication status, species, sex, or sample size; and (3) studies comparing various interventions of curcumin to control groups; and (4) article in English. Additionally, all types of liver cancer, including chemically-induced, cell line-derived, or genetically modified models, were considered for inclusion.

Studies with the following characteristics were excluded from this review: (1) studies that did not include primary experimental data assessing the effect of curcumin on liver cancer cell lines or animal models; or (2) studies appeared in the form of abstracts, comments, reviews, editorials, or similar non-primary research articles.

Study Selection and Inclusion Flowchart was illustrated in Fig. 2.

Fig. 2.

Study selection and inclusion flowchart. The study selection process, from database searches to exclusions and final inclusion of 27 studies

Outcome measurements

The outcomes of interest were extracted from the included studies, which employed various experimental techniques to evaluate the effects of curcumin on liver cancer. These techniques included Western blot (WB), reverse transcription polymerase chain reaction (RT-PCR), flow cytometry, immunohistochemistry, MTT assay, CCK-8 assay, and migration and invasion assays. The data gathered from these studies were used to assess cellular markers, apoptosis, proliferation, and the mechanisms underlying curcumin's protective effects against liver cancer.

Data extraction and quality assessment

Two authors independently extracted the following data from each study: (1) the first author's name and publication year; (2) the species used in the in vivo and in vitro models, including gender and sample size; (3) the cell culture medium used; (4) the interventions of curcumin, including dose, duration, method of dissolution, and administration route; (5) the research methods employed, such as WB analysis and MTT assays; and (6) the potential mechanisms underlying the protective effects of curcumin against liver cancer. To evaluate the quality of the included studies, a six-item scale was applied, based on a previous study [26]. The criteria for this scale included: (A) peer-reviewed publication; (B) random allocation to treatment groups; (C) blinded outcome assessment; (D) sample size calculation; (E) compliance with animal welfare regulations; and (F) a statement of potential conflicts of interest.

Results

Studies selection

A total of 1048 studies were initially retrieved from the three databases, among which 131 were duplicates and excluded (Fig. 2). After further screening the abstracts and titles of the remaining articles, 891 studies were excluded for the following reasons: (1) being comments, reviews, or editorials; (2) were clinical trials; (3) focused on diseases other than liver cancer; (4) outcome measures used did not fit our present study objectives; (5) lacked a control group; or (6) had insufficient data. Following this, 27 studies were found eligible for analysis [27–53].

Study characteristics and experimental models

Following comprehensive assessments of the studies retrieved, a total of 27 studies, comprising 8 in vivo models [27–31, 50], 14 in vitro models [38–52], and 5 studies using both in vivo and in vitro models [34–37, 53], we included for final data analysis. We found that the in vivo studies involved two species and five strains: C3H/HeN mice, Wistar rats, B6C3F1 mice, BALB/c nude mice and C57BL/6 mice [27–33, 50, 53]. Among these, 9 studies [27, 28, 30, 32, 33, 35, 37, 50, 53] used male animals, three studies [29, 31, 34] used female animals [36], and one study included both male and female animals [36]. The detailed characteristics of the included studies are summarized in Tables 1 and 2. Of the 13 studies that conducted in vivo experiments (Table 1), 23.08% [27, 30, 50] employed N-diethylnitrosamine (DEN)-induced liver cancer models, 15.38% [23, 26] used nitrosodiethylamine (NDEA) models, and another 15.38% [28, 34] utilized intraperitoneal injection of liver cancer cells (AH-130 or CBO140C12 cells). The remaining 46.15%of studies employed subcutaneous injection of liver cancer cells, including Bel7402, HepG2, Hepal-6, and H22 cells [31, 33, 35–37].

Table 1.

Basic information of curcumin in the preclinical in vivo models of hepatic carcinoma

Study (years)	Species (Sex, n)	Model	Interventions	Research methods
Chuang (2000)	C3H/HeN mice (Male, 21)	DEN induced (20 μg/g, i.p.)	Curcumin (0.2%) was supplemented in the diet, starting 4 days before DEN injection until death	1. G6Pase biochemical staining 2. WB analysis
Busquets (2001)	Wistar rats (Male, NR)	AH-130 cells (108, i.p.)	Curcumin (20 μg/kg bw dissolved in DMSO: PBS 1:1000, i.p.) for 6 consecutive days	1. Flow cytometry 2. Circulating metabolite analysis
Thapliyal (2003)	Wistar rats (Female, 157)	NDEA induced (200 ppm, in drinking water)	Curcumin (0.2, 1.0 and 5.0%) was supplemented in the diet for 16 or 10 weeks	1. GGT positive foci histochemical staining 2. H and E staining
Shukla (2003)	Wistar rats (Male, 50)	DEN induced (200 ppm, in drinking water)	Curcumin (200 mg/kg) by oral intubation for 5 days	1. Immunohistochemical of GST-P 2. Cytochemical of GGT, ATPase, AIkPase and G6Pase
Ohashi (2003)	B6C3F1 mice (Female, NR)	CBO140C12 cells (200 μl/mice, i.p.)	Curcumin (100 and 200 mg/kg p.o.) was administered daily for 20 days after the implantation	1. Cell invasion assay 2. Gelatin zymography 3. Cell adhesion assay 4. Flow cytometry 5. Haptotactic migration assay 6. Visualization of actin filaments
Cui (2006)	BALB/c nude mice (Female, NR)	Bel7402 cells (107, s.c.)	Curcumin (0-200 mg/kg p.o.) for 5 consecutive weeks	1. Assessment of apoptosis induction 2. Telomerase activity
Sreepriya (2006)	Wistar rats (Male, 36)	NDEA induced (200 mg/kg, i.p.)	Curcumin (100 mg/kg p.o in Tween20 and distilled water) for a period of 14 weeks	1. The assay of lipid peroxide, white blood cells, red blood cells, platelets, hemoglobin 2. Histopathological studies 3. The estimation of lipid peroxides, GSH, GPX and GST
Yoysungnoen (2008)	BALB/c nude mice (Male, 90)	HepG2 cells (2 × 10–6, s.c.)	Curcumin (300 and 3000 mg/kg dissolved in 0.1% DMSO, p.o.)	1. anti-proliferation assay 2. Intravital fluorescence video microscopy 3. Measurement of capillary vascularity
Liu (2012)	C57BL/6 mice (Male, NR)	1. Hepal-6 cells(2 × 106, s.c.) 2. Hepal-6 cells(2 × 106) injected into the spleen	1. EF-24 (20 mg/kg i.p.) for 21 days 2. EF-24 (20 mg/kg i.p.) for one week	1. Tumor-occupied area in excised livers 2. Immunohistochemistry
Dai (2013)	Nude mice (Male and Female, 24)	HepG2 cells (4–6 × 106 s.c.)	Curcumin (20,40,60 mg/kg, i.v.) for 15 days	1. Tumor volume 2. Detection of peripheral blood parameters 3. Detection of liver and kidney function
Pan (2018)	Nude mice (Male, NR)	H22 cells (2 × 105 s.c.)	Curcumin (50, 100 mg/kg dissolved in 0.1% DMSO) for two weeks	1. Histopathology 2. Immunohistochemistry 3. WB analysis 4. RT-qPCR
Mohammed (2021)	CD1 albino mice (Male, 66)	DEN-induced (15 mg/kg for the first 6 weeks, i.p., and 25 mg/kg for the last 9 weeks, i.p.)	Curcumin (10 mg/kg, twice a week, for 15 weeks; orally)	1. Biochemical analysis 2. TNF-α, VEGF, and AFP in the serum 3. Measurement of oxidative stress markers and antioxidant enzymes in the liver 4. Histopathology 5. RT-qPCR

Table 2.

Basic information of curcumin in the preclinical in vitro models of hepatic carcinoma

Study (years)	Species	Medium	Interventions	Research methods
Lin (1998)	SK-Hep-1 cells Huh-7 cells	DMEM, 100 μM NEAA, 10%FBS and antibiotics	Curcumin (5, 10 and 50 μM) for 6 h	1. MTT assay 2. Migration and invasion assay 3. metalloproteinase zymographic assay
Ohashi (2003)	CBO140C12 cells	DMEM/F12, 10%FCS, L-glutamine and 2 g/L glucose	Curcumin (0.1, 0.3, 1, 3 and 10 μM) for different times in different technologies	1. Cell invasion assay 2. Gelatin zymography 3. Cell adhesion assay 4. Flow cytometry 5. Haptotactic migration assay 6. Visualization of actin filaments
Notarbartolo (2005)	HA22T/VGH cells	RPMI1640, 10%FCS, 2 mM L-glutamine, 1 mM sodium pyruvate, 100 units/ml penicillin, 100 μg/ml streptomycin	Curcumin (10, 15, 20 and 25 μM) for different times in different technologies	1. Cell growth assay 2. Cell proliferation assay 3. Flow cytometry 4. NF-kB activation 5. RT-PCR 6. Synergistic cytotoxicity
Kang (2005)	Hep3B cells	RPMI1640, 10%FCS, antibiotics	Curcumin (10, 20, 25, 50 and 100 μM) for different times in different technologies	1. WB analysis 2. HAT assay 3. HDAC assay 4. Measurement of intracellular ROS 5. RT-PCR 6. MTT assay
Cao (2006)	HepG2 cells	MEM, 10%FBS, penicillin, streptomycin	Curcumin (2.5, 5, 10, 20 and 40 μg/ml) for different times in different technologies	1. MTT assay 2. QPCR 3. 8-OHdG immunocytochemistry staining 4. Comet assay 5. Measurement of intracellular ROS 6. Lipid peroxidation assay
Cao (2007)	HepG2 cells	MEM, 10%FBS, penicillin, streptomycin	Curcumin (2.5, 5, 10, 20, 30, or 40 μg/ml) for 1, 6, 10, or 16 h before analysis	1. Hoechst 33,342 staining 2. Annexin V-FITC and PI staining 3. Mitochondrial membrane potential assay 4. Cytochrome c release analysis 5. WB analysis 6. MTT assay
Li (2009)	1.HEP3B, SK-Hep-1 2.SNU449 cells	1. DMEM, 10%FBS, L-glutamine, antibiotics 2. RPMI1640, 10%FBS, L-glutamine, antibiotics	Curcumin (10, 20, 30, and 40 μM) for up to 6 days	1. MTT assay 2. Notch1 RNA interference assay 3. WB analysis 4. Xenograft study
Xiao (2010)	HepG2 cells	DMEM, 10%FBS, 100U/ml penicillin	Various concentrations (5, 10 and 20 μM) of GL63 and curcumin for 48 h	1. MTT assay 2. Apoptosis rate analysis 3. Endoplasmic reticulum calcium pools assay 4. WB analysis
Liu (2012)	1. H22, HUVEC cells 2. Hepal-6 cells	1. RPMI1640, 10%FCS, 1% penicillin–streptomycin 2. DMEM, 10%FCS, 1% penicillin–streptomycin	EF24 (0.5, 1, 2, 4 and 8 μM) for 48 or 72 h	1. CCK8 assay 2. Apoptosis assay 3. Cell cycle analysis 4. WB analysis
Dai (2013)	HepG2 cells	NR	Curcumin(2, 4, 8, 16, 32 and 64 μM) for 24, 36 and 48 h	1. MTT assay 2. Caspase-3 activity analysis
Marquardt (2015)	PLC/PRF5, WRL68, Huh7, KMCH cells	DMEM, 10%FCS, 2 mM L-glutamine, penicillin/streptomycin	Curcumin(25 μM) for 3 days	1. WST-1 and apoptosis assay 2. colony formation and matrigel-based sphere assay 3. SP analysis 4. WB analysis and EMSA 5. Microarray analysis 6. RT-PCR
Zhang (2017)	SMMC-7721 cells	DMEM, 10%FBS, penicillin/streptomycin	Curcumin(10, 20 and 40 mmol/L) for 12, 24 and 48 h	1. MTT assay 2. Flow cytometry 3. WB analysis
Pan (2018)	H22 cells	DMEM, 10%FCS, 100U/ml penicillin, 100 μg/ml streptomycin	Curcumin(5, 10, 20, 40 and 80 μM) for 12, 24, or 48 h	1. CCK8 assay 2. Apoptosis assay
Wang (2018)	HCCLM3, HepG2, Huh7 cells	DMEM, 10%FBS, antibiotics	Curcumin or WZ35(5, 10, 20, 30 and 40 μg/ml) for 12 or 24 h	1. CCK8 assay 2. Transwell migration and invasion assay 3. Cell total ROS determination 4. DAPI staining 5. WB analysis
Ren (2018)	HepG2 cells	RPMI-1640, 10%FBS, penicillin/streptomycin	Curcumin(20, 50, 80 and 100 μM) for 24, 48 and 72 h	1. CCK8 assay 2. Wound-healing assay 3. Transwell migration assay 4. Flow cytometric 5. WB analysis 6. ELISA assay
Wang (2018)	HepG2 cells	DMEM, 10%FBS	Curcumin(10, 20, 40 or 80 μM) for 24 h	1. MACS 2. MTT assay 3. Apoptosis detection 4. WB analysis
Liang (2021)	HepG2 cells	DMEM, 10%FBS, 1% penicillin/streptomycin	Curcumin(0, 5, 10, 20 or 30 μM) for 12 h and 20 μM for 0, 3, 6, 9, 12 h	1. Fluorescence microscopy 2. Flow cytometry 3. DHE (1 μM/ml) 4. LDH cytotoxicity assay 5. PI icorporation 6. WB analysis
Chen (2022)	LO2 and HepG2 cells	High-glucose DMEM, 12% FBS, 1% penicillin/streptomycin	Curcumin(0, 20, 40, and 60 μmol/L) for 24 h	1. MTT assay 2. Flow cytometry 3. Transmission electron microscopy 4. WB assay 5. RT-PCR

A total of 7 studies [29, 31, 33, 34, 36, 37] reported a dose gradient of curcumin. However, the method of curcumin administration was found to vary across the included studies. For instance, 8 studies [27, 29–34, 50] administered curcumin orally, 2 [28, 35] used intraperitoneal injection, 1 used intravenous injection [36], 1 used intragastric administration [53]. However, 1 study [37] did not specify the administration method. Additionally, 3 studies [28, 33, 37] dissolved curcumin in DMSO.

In the in vitro studies (Table 2), a total of 16 different cell lines were used, including SK-Hep-1 [38, 42], Huh-7 [38, 44, 46], CBO140C12 [34], HATT/VGH [39], Hep3B [40, 42, 53], HepG2 [36, 41, 43, 46–49, 51–53], SNU449 [42], H22 [35, 37], HUVEC [35], Hepal-6 [35], PLC/PRF5 [42], WRL68 [42], KMCH [42], SMMC-7721 [47], HCCLM3 [46], and LO2 cells [52]. The culture media for each cell line are presented in Table 2. All of the in vitro studies included a dose gradient of curcumin. Various experimental techniques were employed to explore the effects of curcumin, including immunohistochemistry (IHC), transwell migration and invasion assays, adhesion assays, and various staining methods such as G6Pase biochemical staining, GGT-positive foci histochemical staining, and H&E staining. Additionally, techniques such as Western blotting, flow cytometry, and RT-PCR were used to investigate the potential mechanisms underlying curcumin’s protective effects.

Quality assessment of included studies

Table 3 provides a summary of the quality assessment of the studies included in this review, demonstrating scores ranging from 2 to 5 of a possible 6 points. Among them, 1 study [44] achieved a score of 5 points (3.85%), 13 studies [27–29, 39–41, 45, 46, 49–53] got 4 point, 7 studies [31, 34, 38, 42, 43, 47, 48] received 3 points (26.92%), and 6 studies [30, 32, 33, 35–37] scored 2 points (23.08%). All the included studies were peer-reviewed publications and complied with animal welfare regulations. However, none of the studies reported a sample size calculation. Of the 27 studies, 21 indicated that random allocation to groups was employed, 8 used a blinded assessment of outcomes, and 7 provided a statement regarding potential conflicts of interest.

Table 3.

Quality assessment of the included studies

Study	A	B	C	D	E	F	Total
Lin (1998)	✓	✓			✓		3
Chuang (2000)	✓	✓	✓		✓		4
Busquets (2001)	✓	✓	✓		✓		4
Thapliyal (2003)	✓	✓	✓		✓		4
Shukla (2003)	✓				✓		2
Ohashi (2003)	✓	✓			✓		3
Notarbartolo (2005)	✓	✓	✓		✓		4
Kang (2005)	✓	✓	✓		✓		4
Sreepriya (2006)	✓				✓		2
Cui (2006)	✓	✓			✓		3
Cao (2006)	✓	✓	✓		✓		4
Cao (2007)	✓	✓	✓		✓		4
Yoysungnoen (2008)	✓				✓		2
Li (2009)	✓	✓			✓		3
Xiao (2010)	✓	✓			✓		3
Liu (2012)	✓				✓		2
Dai (2013)	✓				✓		2
Marquardt (2015)	✓	✓	✓		✓	✓	5
Zhang (2017)	✓	✓			✓	✓	4
Pan (2018)	✓				✓		2
Wang (2018)	✓	✓			✓	✓	4
Ren (2018)	✓	✓			✓		3
Wang (2018)	✓	✓			✓		3
Mohammed (2021)	✓	✓			✓	✓	4
Liang (2021)	✓	✓			✓	✓	4
Chen (2022)	✓	✓			✓	✓	4

Molecular mechanisms underlying curcumin’s protective effects

The main outcome measures and results from the included studies are summarized in Table 4. It can be observed that the involvement of NF-kB was investigated in 6 studies [32, 38, 39, 44, 47, 50], while caspase-3 expression was examined in 4 studies [35, 36, 43, 48]. The proteins Bcl-2 and Bax were evaluated in 4 studies [35, 45, 48, 53], and cytochrome c, Cdc2, and COX-2 were assessed in 2 studies [41, 48]. Additionally, the levels of cyclin B1, c-Myc, Bcl-X_L, Bcl-X_S, Notch1, Survivin, caspase-9, AP-1, antioxidant enzymes, VEGF, JNK, MMP-9, MMP-2, and histone H₃ and H4 were examined in 10 studies [32, 35, 38–40, 42, 45, 46, 48, 53]. An illustration of the protective mechanisms of curcumin in liver cancer is provided in Figs. 3 and 4.

Table 4.

Main outcome measures of the included studies

Study (years)	Outcome measures	Protection mechanism
Lin (1998)	1. Curcumin inhibited the invasion and migration of highly invasive human HCC SK-Hep-1 cells 2. Curcumin inhibited the invasion through inhibition of MMP-9 secretion	Anti-inflammatory
Chuang (2000)	1. Curcumin inhibited multiplicity and incidence of HCC 2. Curcumin reversed the levels of p21ras, PCNA and CDC2 back to normal	Pro-apoptosis
Busquets (2001)	1. Curcumin decreased tumor growth 2. Curcumin resulted in a significant decrease in heart weight 3. Curcumin resulted in a decrease in both glucose and triacylglycerols	Phenomenon research
Thapliyal (2003)	1. Curcumin protected against NDEA-induced increase in absolute and relative liver weights 2. Curc umin reduced the number of NDEA-induced big-sized foci	Phenomenon research
Shukla (2003)	1. Curcumin decreased the area positive for GST-P and GGT foci 2. Curcumin potentiated the development of ATPase-, AlkPase-, and G6Pase-positive foci	Phenomenon research
Ohashi (2003)	1. Curcumin inhibited the integrin-mediated cell adhesion 2. Curcumin targeted metastasis-specific processes 3. Curcumin induced the alteration of stress-fiber formation	Anti-metastasis
Notarbartolo (2005)	1. Curcumin has antitumor and cell death effects 2. Curcumin activated NF-KB 3. Curcumin down-regulated the mRNA levels of COX-2, c-myc and Bcl-XL 4. Curcumin up-regulated the mRNAs of Livin, Bcl-XS and c-IAP-2	Anti-inflammatory, pro-apoptosis
Kang (2005)	1. High concentration of curcumin promoted ROS generation 2. ROS generation is involved in the curcumin inhibition of histone acetylation, where HAT serves as the target molecule 3. Inhibition of HAT activity represents one mechanism for curcumin to exert its in vivo functions	Inhibition of histone acetylation
Sreepriya (2006)	1. Curcumin inhibited the lipid peroxidation chain reaction 2. Curcumin increased the activities of antioxidant enzymes to cope with the oxidative stress	Antioxidant capabilities, anti-inflammatory
Cui (2006)	1. Curcumin produced a dose-dependent inhibition of tumor growth 2. Curcumin inhibited telomerase activity	Pro-apoptosis
Cao (2006)	1. Curcumin inhibited the growth of HepG2 cells in a concentration and time-dependent manner 2. Curcumin led to dose-dependent DNA damage to both mtDNA and nDNA 3. Curcumin increased 8-OHdG content in both mtDNA and nDNA 4. Curcumin induced DNA strand breaks in HepG2 cells	Phenomenon research
Cao (2007)	1. Curcumin induced apoptosis through fully functional mitochondria 2. Curcumin promoted cytochrome c release 3. Curcumin induced typical chromatin condensation and nuclear fragmentation 4. Curcumin increased the number of apoptotic cells	Pro-apoptosis
Yoysungnoen (2008)	1. Curcumin reduced the appearance of neocapillaries induced by HepG2 2. Curcumin attenuated the abnormalities of neocapillaries network pattern 3. Curcumin had dose-dependent anti-angiogenic effects	Phenomenon research
Li (2009)	1. Curcumin inhibited Notch1, led to a dose-dependent decrease in the expression of NICD 2. Curcumin had a profound dose-dependent inhibition of cell growth	Pro-apoptosis
Xiao (2010)	1. GL63, depleted ER calcium strorage 2. GL63 activated ER stress pathway	Pro-apoptosis
Liu (2012)	1. EF24 inhibited cell proliferation and reduced cell viability 2. EF24 induced cell cycle arrest 3. EF24 inhibited angiogenesis and tumor cell survival signaling	Pro-apoptosis, anti-angiogenesis
Dai (2013)	1. Curcumin possessed a dose-dependent cell inhibition effect 2. Curcumin activated caspase-3 3. Curcumin inhibited the growth of liver cancer	Pro-apoptosis
Marquardt (2015)	1. Curcumin suppressed hepatoma cell growth depending on the extent of NF-kB inhibition 2. Curcumin exerted TIC depleting activity	Anti-inflammatory
Zhang (2017)	1. Curcumin decreased the cell proliferation activity 2. Curcumin increased the cell quantities in the G1 cycle and reduced cell numbers in the S cycle 3. Curcumin decreased the expression of Bcl-2 and Survivin protein and increased the Bax expression 4. Curcumin activated AMPK signaling pathway	Pro-apoptosis
Pan (2018)	1. Curcumin inhibited proliferation 2. Curcumin inhibited tumor growth by targeting VEGF expression 3. Curcumin inhibited VEGF protein expression and PI3K/AKT signaling	Pro -apoptosis
Wang (2018)	1. WZ35 suppressed the proliferation of human hepatocellular cell 2. WZ35 suppressed HCC cell migration and invasion 3. WZ35 induced JNK activation is ROS-dependent	Anti-metastasis
Ren (2018)	1. Curcumin inhibits proliferation, migration, and invasion 2. Curcumin halted the cell cycle in the S phases 3. Curcumin reduced the expression of HSP70 and TLR4	Anti-inflammatory, pro-apoptosis
Wang (2018)	1. Curcumin inhibits the proliferation of liver cancer stem cells 2. Curcumin increased the protein levels of caspase-3, caspase-9 and Bax, decreased the Bcl-2 3. Curcumin decreased the release of cytochrome c 4. Curcumin inhibited the activation of the PI3K/AKT/mTOR signaling pathway	Pro-apoptosis
Mohammed (2021)	1. Curcumin led to a significant decline in ALT and ALP activities and increased albumin level 2. Curcumin decreased TNF-α level, VEGF level, AFP level 3. Curcumin augmented the SOD, catalase, GPx activity, but reduced GSH, MDA level 4. Curcumin downregulated NF-kB, P53	Anti-oxidant Anti-inflammatory Anti-angiogenic
Liang (2021)	1. Curcumin increased cellular ROS levels and induced apoptosis 2. Curcumin induced lytic cell death and pyroptosis	Pro-apoptosis
Chen (2022)	1. Curcumin exerted an obvious inhibitory effect on the proliferation of hepatoma cells 2. Curcumin induced the apoptosis 3. Curcumin promoted apoptosis through the p53 pathway	Pro-apoptosis

HCC Hepatocellular carcinoma; MMP-9 Matrix metalloproteinase-9; NDEA nitrosodiethylamine; GST-P placental isozyme of glutathione S-transferase; GGT gamma glutamyltranspeptidase; ROS Reactive oxygen species; HAT Histone acetyltransferase; 8-OHdG 8-hydroxydeoxyguanosine; TIC tumor-initiating cells; VEGF vascular endothelial growth factor; ER endoplasmic reticulum; NICD Notch1 Intracellular Domain; GL63/EF24/WZ35 a kind of curcumin analog

The studies that observed anticancer effects but did not specify the exact mechanisms were defined as phenomenon research

Fig. 3.

Protective mechanisms of curcumin in liver cancer. A summary of the key mechanisms through which curcumin affects liver cancer。including apoptosis, inflammation, oxidative stress, angiogenesis, metastasis, and histone acetylation. The X-axis represents curcumin's effects in liver cancer, and the Y-axis indicates the number of studies mentioning each effect

Fig. 4.

Proposed mechanistic model of curcumin’s therapeutic effects in liver cancer. This schematic representation illustrates the molecular mechanisms via which curcumin exerts its therapeutic effects in liver cancer models. Curcumin can modulate apoptosis by upregulating pro-apoptotic proteins (Bax, caspase-3) and downregulating anti-apoptotic markers (Bcl-2, Survivin). It can also inhibit inflammatory pathways by suppressing NF-κB activation, reduce oxidative stress by enhancing antioxidant enzyme activity, and mitigate metastasis by downregulating MMP-2 and MMP-9 while increasing E-cadherin expression

Pro-apoptotic properties of curcumin

A total of 15 studies demonstrated that curcumin exerts pro-apoptotic effects in liver cancer models, both in vivo and in vitro. For instance, Cui et al. [31] reported the formation of apoptotic bodies in curcumin-treated HL60 cells, as observed through flow cytometric analysis. This observation was supported by the presence of a subdiploid peak, which indicates the appearance of apoptotic nuclei resulting from partial DNA loss due to the leakage of low-molecular-weight fragments during apoptosis. Similarly, Liu et al. [35] showed that curcumin treatment reduced the expression levels of cyclin B1, Cdc2, and the Bcl-2/Bax ratio in comparison to the control group. In another study, Dai et al. [36] demonstrated a dose-dependent pro-apoptotic effect of curcumin in HepG2 cells, with increasing doses significantly elevating the apoptosis rate (p < 0.05) and enhancing caspase-3 activity, particularly at concentrations of 4 μM (p < 0.05), 8 μM (p < 0.01), and 16 μM (p < 0.01).

Pan et al. [37] further confirmed curcumin’s pro-apoptotic activity, showing a significant induction of apoptosis in H22 cells at doses of 40 μM (p < 0.05) and 80 μM (p < 0.01). Notarbartolo et al. [39] found that curcumin treatment led to a decrease in the mRNA levels of cyclooxygenase-2 (COX-2) and myelocytomatosis viral oncogene homolog (c-Myc) (to 39% and 25% of control levels, respectively), while simultaneously increasing the levels of Livin (192% of control), Bcl-XS (185% of control), and inhibitor of apoptosis protein 2 (c-IAP-2) (195% of control). Additionally, Cao et al. [41] observed typical apoptotic morphological changes in HepG2 cells and noted the release of cytochrome c from the mitochondria after exposure to curcumin for 10 h. Li et al. [42] demonstrated that curcumin-induced apoptosis inhibited HCC cell growth through the downregulation of Notch1 signaling. Similarly, Xiao et al. [43] showed that curcumin dose-dependently increased the apoptotic rate in GL63 cells, as measured by flow cytometry.

As further evidence supporting curcumin's pro-apoptotic effects, Zhang et al. [45] found that curcumin significantly decreased the expression levels of Bcl-2 and Survivin, while significantly increasing Bax levels (p < 0.05). Ren et al. [47] also reported that curcumin treatment at concentrations of 50 and 80 μM significantly increased the apoptosis rate compared to the control group (p < 0.001). Wang et al. [48] showed that the apoptosis rate in the control group was 1.23% ± 0.35%, while treatment with 20 μM curcumin resulted in a significant increase to 11.37 ± 1.04% (p < 0.001). Additionally, curcumin treatment led to a significant increase in Bax expression (p < 0.001) and a significant decrease in Bcl-2 (p < 0.01). Notably, the release of cytochrome c from mitochondria was also observed, with mitochondrial cytochrome c levels decreasing from 0.95 ± 0.08 in the control group to 0.52 ± 0.08 (p < 0.01), while cytoplasmic cytochrome c levels significantly increased from 0.95 ± 0.08 to 0.52 ± 0.08 (p < 0.001).

Anti-inflammatory properties of curcumin in liver cancer

A total of 5 studies reported on the anti-inflammatory effects of curcumin in liver cancer models. Sreepriya et al. [32] showed that curcumin inhibited the activation of NF-κB, possibly through modulation of XIAP. Similarly, Lin et al. [38] suggested that curcumin's anti-inflammatory activity is mediated by its inhibition of both NF-κB and AP-1 pathways. Notarbartolo et al. [25] further supported these findings, reporting that curcumin reduced NF-κB activity after 16 h of treatment (p < 0.01). Marquardt et al. [44] demonstrated that curcumin’s inhibition of NF-κB correlated with the suppression of liver cancer cell growth. Additionally, Ren et al. [47] found that curcumin suppressed toll-like receptor 4 (TLR4) expression in cancer cells by downregulating the levels of heat shock protein 70 (HSP70), which inhibited the NF-κB signaling pathway.

Curcumin as an antioxidant and anti-angiogenic agent

In our review, one study reported on curcumin's antioxidant properties. Sreepriya et al. [32] demonstrated that curcumin inhibited the lipid peroxidation chain reaction and upregulated the activities of antioxidant enzymes such as glutathione (GSH), glutathione peroxidase (GPX), and glutathione S-transferase (GST). These findings highlight curcumin’s potential to counteract oxidative stress in liver cancer. Furthermore, one study conducted by Liu et al. [35] reported that curcumin, through the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) and extracellular regulated protein kinases (ERK)-MAPK signaling pathways, could inhibit liver cancer cell growth, thereby indicating that curcumin may possess anti-angiogenic properties. In addition, the study observed significantly decreased levels of VEGF and COX-2, further suggesting curcumin's anti-angiogenic capability.

Curcumin's anti-metastatic effects and epigenetic regulation

Two studies in our review highlighted curcumin's potential anti-metastatic effects. Ohashi et al. [34] reported that curcumin administration (100 and 200 mg/kg, p.o.) for 20 days dose-dependently inhibited intrahepatic metastasis (p < 0.001). Additionally, curcumin significantly suppressed cell adhesion to Matrigel and type IV collagen, indicating a reduction in integrin-mediated cell adhesion, a key step in metastasis. Wang et al. [46] further demonstrated that WZ35, a curcumin analog, reduced the levels of MMP-2, MMP-9, and N-cadherin, while increasing E-cadherin expression. These changes, coupled with the activation of the JNK signaling pathway, contributed to the suppression of tumor cell invasion and migration. In addition to its anti-metastatic effects, one study reported that curcumin can inhibit histone acetylation. Kang et al. [40] showed that curcumin decreased histone acetylation in a concentration- and time-dependent manner by suppressing histone acetyltransferase (HAT) activity. These findings suggest that curcumin may play a role in epigenetic regulation, further contributing to its therapeutic potential in liver cancer.

Discussion

This systematic review included 27 preclinical studies, which involved 8 in vivo models, 14 in vitro models, and 5 studies employing both in vivo and in vitro models. The results suggest that curcumin, compared to control treatments, could reduce liver cancer tumor size, weight, and metastasis—both intrahepatic and extrahepatic. These effects appear to be mediated through multiple mechanisms, including pro-apoptotic, anti-inflammatory, antioxidant, anti-angiogenic, anti-metastatic properties, and the inhibition of histone acetylation.

The anti-cancer roles of curcumin in liver cancer

Based on the observed results, a proposed mechanistic model of curcumin's therapeutic effects in liver cancer is shown in Fig. 4. Briefly, some of the key pathways reported include: (1) downregulation of pro-survival proteins such as Bcl-2, cyclin B1, Cdc2, c-Myc, and Survivin, coupled with the upregulation of pro-apoptotic factors like caspase-3, caspase-9, Bax, and Livin to promote apoptosis [54]; (2) activation of NF-κB and downregulation of AP-1 to modulate inflammatory pathways [55]; (3) inhibition of lipid peroxidation and enhancement of antioxidant enzyme activity to exert antioxidant effects [56]; (4) suppression of COX-2 and VEGF expression to reduce angiogenesis [57]; (5) upregulation of JNK, MMP-9, and MMP-2 to prevent metastasis [58]; and (6) inhibition of histone acetylation via downregulation of histone H3 and H4 expression [59]. However, despite these insights, further research is needed to fully characterize the molecular mechanisms through which curcumin exerts its protective effects in liver cancer.

The anti-apoptotic role of curcumin in liver cancer

One of the most consistent findings in the reviewed studies was curcumin's ability to induce apoptosis in liver cancer models, both in vivo and in vitro. 16 studies demonstrated that curcumin treatment resulted in the formation of apoptotic bodies, a hallmark of apoptosis. Curcumin's pro-apoptotic effects were dose-dependent, with higher doses often yielding more pronounced effects. These findings are consistent with previous reports that curcumin modulates key apoptotic markers, such as the Bax/Bcl-2 ratio, caspase-3 activation, and cytochrome c release. The observed increase in apoptosis may help explain the reduction in tumor cell proliferation and the inhibition of liver cancer progression. Despite the consistent pro-apoptotic effect, variability in the response to curcumin was observed across studies, which could be attributed to the dose gradients used in the studies, which included oral, intraperitoneal, and intravenous administrations, suggesting that curcumin's anti-cancer activity is both dose- and method-dependent [60].

The anti-inflammatory role of curcumin in liver cancer

Inflammation plays a crucial role in the development and progression of liver cancer [61]. The anti-inflammatory effects of curcumin were explored in five studies included in our analysis. Curcumin has been shown to inhibit the activation of NF-κB, a central regulator of inflammatory pathways, in liver cancer models [62]. This effect was consistently observed in multiple studies, suggesting that curcumin exerts its anti-inflammatory actions via suppression of NF-κB activation, possibly through modulation of other signaling molecules such as XIAP and TLR4. These findings are in line with previous reports that curcumin's anti-inflammatory properties may contribute to its anti-cancer effects by reducing the inflammatory microenvironment that promotes tumorigenesis. Wehile curcumin's anti-inflammatory effects were well-documented, the variation in specific pathways and molecules involved across studies suggests that curcumin may act through multiple mechanisms to modulate the inflammatory response, and further research is needed to clarify the exact molecular targets. Additionally, the duration of curcumin treatment may influence the extent of its anti-inflammatory effects, warranting further exploration in future studies.

The anti-antioxidant role of curcumin in liver cancer

Curcumin's antioxidant activity is another key feature that contributes to its therapeutic potential in liver cancer [63]. One study reported that curcumin inhibited lipid peroxidation and enhanced antioxidant enzyme activity, including glutathione peroxidase and glutathione S-transferase [56]. These findings suggest that curcumin may reduce oxidative stress, which is a key contributor to liver cancer development. The antioxidant properties of curcumin may also help prevent DNA damage and mutation [63], thereby limiting tumor progression. In addition to its antioxidant effects, curcumin has shown potential as an anti-angiogenic agent, as demonstrated by the decreased levels of VEGF and COX-2 in treated liver cancer cells [63]. By inhibiting angiogenesis, curcumin may prevent the growth of new blood vessels that supply nutrients to the tumor, thereby limiting tumor growth and metastasis. Moreover, a recent clinical study [64] involving 80 primary liver cancer patients evaluated curcumin alongside TACE. The treatment group, receiving both curcumin and TACE, showed significantly higher remission (47.5% vs. 25%) and control rates (97.5% vs. 82.5%, p < 0.05), along with improvements in tumor size, serum AFP, liver function, and quality of life (KPS). Additionally, the treatment group had better survival and lower recurrence rates at 0.5, 1, and 2 years (p < 0.05). These findings support curcumin's potential as an adjunct to TACE, warranting further clinical investigation. However, while these effects are promising, only one study in this review assessed curcumin's anti-angiogenic activity, highlighting the need for further research to confirm its role in this process.

The anti-metastatic role of curcumin in liver cancer

The anti-metastatic potential of curcumin was explored in two studies, both of which reported significant inhibition of liver cancer metastasis following curcumin treatment. Curcumin was shown to reduce cell adhesion to extracellular matrix components, such as Matrigel and type IV collagen, which are critical steps in metastasis. Moreover, curcumin treatment led to decreased expression of matrix metalloproteinases (MMP-2 and MMP-9) and the adhesion molecule N-cadherin, while increasing expression of the epithelial marker E-cadherin. These findings suggest that curcumin may suppress liver cancer cell invasion and migration by modulating the epithelial-mesenchymal transition (EMT) [65], a process essential for metastasis. However, as only two studies assessed curcumin’s anti-metastatic effects, more research is needed to validate these findings and better understand the underlying mechanisms.

Current challenges

Although curcumin has shown promising results in preclinical models, it is important to note that the applicability of these findings to human liver cancer remains uncertain. Therefore, more clinical studies, particularly randomized controlled trials (RCTs), are needed to confirm the therapeutic potential of curcumin in humans. The studies included in this review exhibited some degree of heterogeneity in terms of experimental design, curcumin dosage, administration methods, and outcome measures. While heterogeneity was not explicitly quantified in the statistical analysis, the variation in study characteristics highlights the need for standardized protocols in future research.

Regarding study quality, most of the included studies were peer-reviewed, employed random allocation to treatment groups, and adhered to animal welfare regulations. However, none of the studies reported sample size calculations, which is a limitation that could affect the statistical power of the results. Additionally, only a subset of studies employed blinded outcome assessments, which may introduce bias in interpreting the results. Future studies could aim to improve methodological rigor, particularly with respect to randomization, blinding, and sample size calculations, to enhance the validity and reliability of their findings.

Furthermore, curcumin faces pharmacokinetic limitations such as low bioavailability and rapid metabolism. Current research primarily focuses on discussing curcumin's anticancer effects, yet drug development based on curcumin remains limited. The nanodelivery system represents a promising drug delivery technology with broad application prospects, which can enhance drug bioavailability and achieve sustained drug release [66, 67]. Therefore, future research could focus on exploring the construction and application of curcumin nanoparticles to enhance its clinical prospects.

Limitations of the systematic review

While this review provides valuable insights into curcumin's potential as a therapeutic agent for liver cancer, several limitations must be acknowledged. First, the inclusion of only English-language articles may have introduced selective bias by excluding relevant studies published in other languages. Second, the quality of the included studies varied, with scores ranging from 2 to 5 on a 6-point scale, potentially impacting the reliability of the results. Additionally, the significant heterogeneity across study designs, curcumin dosages, and outcome measures hindered our ability to perform a meta-analysis, limiting the statistical robustness of our conclusions. Furthermore, as no clinical trials were included, the effects of curcumin on human liver cancer remain unclear, and the preclinical nature of many studies poses challenges in translating these findings to clinical practice. To address these limitations, future research should focus on well-conducted clinical trials to validate the therapeutic potential of curcumin in liver cancer treatment, as well as investigate its molecular mechanisms and potential synergistic effects with conventional therapies.

Conclusions

In this systematic review, curcumin was shown to exhibit a range of beneficial properties in the treatment of liver cancer, including pro-apoptotic, anti-inflammatory, antioxidant, anti-angiogenic, anti-metastatic effects, and inhibition of histone acetylation (Fig. 5). The preclinical evidence strongly supports the potential of curcumin as a therapeutic agent, particularly for patients with advanced liver cancer who are not candidates for surgery. However, additional high-quality clinical trials are necessary to verify the effectiveness of curcumin in human liver cancer and to address the current gaps in knowledge regarding its optimal use.

Fig. 5.

Curcumin’s working model in liver cancer. Curcumin’s therapeutic effects in liver cancer models, highlighting its influence on apoptosis, inflammation, oxidative stress, and metastasis

Abbreviations

DEN

N-diethylnitrosamine

NDEA

Nitrosodiethylamine

i.p.

Intraperitoneally

s.c.

Subcutaneous injection

i.v.

Intravenous injection

p.o.

Orally

WB

Western blot

GGT

Gamma glutamyltransferase

GST-P

Placental isozyme of glutathione S-transferase

GSH

Glutathione

GPX

Glutathione peroxidase

GST

Glutathione-S-transferase

NR

No report

DMSO

Dimethyl sulfoxide

RT-qPCR

Reverse transcription-polymerase chain reaction

MEM

Minimum essential Eagle's medium

FBS

Fetal bovine serum

MTT

3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide

Q-PCR

Quantitative polymerase chain reaction

8-OHdG

8-Hydroxydeoxyguanosine

ROS

Reactive oxygen species

PI

Propidium iodide

DMEM

Dulbecco's modified Eagle medium

RPMI-1640

Roswell Park Memorial Institute 1640

FCS

Fetal calf serum

CCK-8

Cell counting kit-8

WST-1

Water soluble tetrazolium-1

SP

Side population

EMSA

Electrophoretic mobility shift assay

DAPI

4′,6-Diamidino-2-phenylindole

ELISA

Enzyme-linked immunosorbent assay

MACS

Magnetic-activated cell sorting

HAT

Histone acetyltransferase

HDAC

Histone deacetylase

NEAA

Nonessential amino acids

TIC

Tumor-initiating cells

VEGF

Vascular endothelial growth factor

ER

Endoplasmic reticulum

NICD

Notch1 intracellular domain

GL63/EF24/WZ35

A kind of curcumin analog

Author contributions

K-M and J-HH conceived and designed the study, conducted the database searches, and contributed to drafting the manuscript. Y-S extracted and assessed the studies and assisted in drafting the manuscript. K-M and J-BL provided guidance and revised the manuscript. X-RZ participated in the conceptualization and design of the review and contributed to its revision. All authors read and approved the final manuscript.

Funding

Not applicable.

Data availability

The data underlying this article will be shared on reasonable request to the corresponding author.

Declarations

Ethics approval and consent to participate

Not applicable.

Competing interests

The authors declare no competing interests.