New Structural Analogue of Curcumin, GO-Y030, Exhibits Growth Suppressive Potentials to Human Liver Cancer

Abstract

Liver cancer remains one of the most prevalent malignant tumors globally, with increasing incidence in recent years. While surgical and chemotherapy treatment exist, high recurrence rates and low sensitivity to chemotherapeutic agents persist, leading to consistently low five-year survival rates. Natural compounds with complex structures and diverse biological activities serve as crucial sources for discovering novel liver cancer therapeutics. Curcumin, derived from the turmeric, has demonstrated significant anticancer properties. GO-Y030, a novel curcumin analogue, has been shown to possess superior anticancer activity compared to curcumin in several studies. However, it potential in liver cancer remains underexplored. This research reveals that GO-Y030 significantly inhibits the proliferation of cultured HepG2 liver cancer cells. Moreover, GO-Y030 inhibited the liver cancer growth dose-dependently in in vivo. Preliminary mechanistic study suggested that increased P53 expression may contribute to the antitumor activity of GO-Y030. Thes findings indicate that GO-Y030 holds clinical potential as a novel therapeutic strategy for liver cancer.

Keywords: Curcumin, GO-Y030, Liver cancer, Tumor, Chinese herbs

Introduction

Despite rapid technological advancements, cancer persists as a global health challenge, remaining a leading cause of mortality worldwide. In 2020, cancer accounted for nearly one-sixth of global deaths¹. Among various malignancies, liver cancer ranks as the sixth most common cancer and the fourth leading cause of cancer-related deaths globally². Nearly 830,200 people died from liver cancer in 2020 alone³. The disease burden is particularly severe in China, where liver cancer represents both the fourth most common cancer and the second leading cause of cancer mortality⁴. Liver cancer has drawn great attention from scientists, and has become the focus of many researchers for decades as a cancer with an extremely high mortality rate.

Traditional Chinese herbs have demonstrated significant therapeutic potential, including inhibiting liver cancer cell growth and inducing apoptosis⁵. Increasing research focuses on Chinese herbal medicines for cancer treatment. Certain herbs like Salvia miltiorrhiza and Curcuma zedoary have shown unique advantages in liver cancer therapy by shortening treatment duration and prolonging survival⁶. Curcuma longa, a rhizomatous plant from the Zingiberaceae family native to South Asia. Curcumin, a polyphenolic compound derived from Curcuma longa, exhibits both antioxidant and antibacterial properties. Extensive research has demonstrated its ability to suppress angiogenesis and metastasis across various animal tumor models^{7’8’9’10} This compound displays a broad spectrum of therapeutic benefits at relatively high doses¹¹. Studies reveal curcumin’s potent anticancer activity through multiple pathways: inhibition of growth factors and cellular proliferation, coupled with the promotion of apoptotic cell death¹². Notably, curcumin has shown clinical efficacy against diverse malignancies, including gastric, ovarian, and cutaneous cancers¹². 

Despite promising preclinical research, curcumin has not yet received approval as a chemotherapeutic agent. This limitation primarily stems from its poor bioavailability, which arises from several factors: inadequate gastrointestinal absorption, limited tissue distribution, rapid metabolic breakdown, and swift systemic clearance¹³. To address these challenges, researchers have developed various strategies, including the synthesis of novel curcumin analogs¹⁴. One notable derivative is GO-Y030^{15’16’17’18}, which exhibits more than 10-fold greater antitumor activity compared to curcumin (GI50 = 0.3 μM against human colon carcinoma HCT116 cells)¹⁹. Notably, GO-Y030 demonstrates enhanced modulation of multiple oncoproteins regulated by curcumin. Specifically, it effectively downregulates key proteins including β-catenin, ErbB-2, c-Myc, cyclin D1, and Ki-Ras, while simultaneously inhibiting critical signaling pathways such as NF-κB, PI3K/AKT, JAK/STAT3, and IRF4^16’20’21. The compound’s antitumor potential is further validated by its demonstrated chemopreventive effects in familial adenomatous polyposis (FAP) mouse models, with no detectable in vivo toxicity. In this study, we evaluated the inhibitory efficacy of GO-Y030 in human liver cancer and found that GO-Y030 exerts potent suppressive effects on liver cancer cells both in vitro and in a mouse xenograft model. These findings suggest that this synthetic curcumin derivative holds promise as a potential therapeutic agent for liver cancer.

Materials and Methods

Preparation of Cell Culture Medium

DMEM preparation: Weigh the required amount of DMEM powder (Thermo Fisher Scientific, 12800-017) for preparing 10 L of solution. Dissolve the powder in double-distilled water containing 37 g/L NaHCO₃ (Sangon Biotech, A100865-0500) while stirring thoroughly. Adjust the final volume to 10 L with double-distilled water and use hydrochloric acid to adjust the pH to 7.2-7.4. Sterile-filter the solution, aliquot into sterile containers, and store at 4°C.

Cell Lines

The human hepatocellular carcinoma HepG2 cell line was purchased from the American Type Culture Collection (ATCC). Cells were cultured in Dulbecco’s Modified Eagle Medium (DMEM) supplemented with 10% fetal bovine serum (FBS) (Biological Industries, 04-001-1ACS), 1% Penicillin-Streptomycin Solution (Biological industries, B03-050-1A). All cells were incubated at 37°C in a humidified atmosphere containing 5% CO₂.

Cell Thawing

Preheat the DMEM medium supplemented with 10% FBS and 1% penicillin-streptomycin solution in a 37°C water bath. Retrieve the frozen cell vial from liquid nitrogen storage or -80°C freezer and immediately transfer it to a 37°C water bath. Gently agitate the cryovial in the water bath until complete thawing is achieved (typically within 1-2 minutes). Using a sterile pipette, transfer 8 mL of prewarmed DMEM medium into a 10 cm cell culture dish. Carefully add the thawed cell suspension to the medium, gently mix by pipetting up and down 2-3 times, and incubate the dish in a 37°C, 5% CO₂ incubator. The following day, replace the culture medium by carefully aspirating the old medium and adding fresh prewarmed medium. If cellular attachment or viability appears suboptimal, supplement the medium with additional FBS (up to 20%) as needed.

Cell Passaging

Assess cell density and morphology using an inverted phase-contrast microscope. Proceed with passaging when cells reach > 90% confluency. Briefly, pre-warm DMEM medium, 1× phosphate-buffered saline (PBS, Gibco, 10010023), and 0.25% trypsin-EDTA solution in a 37°C water bath for 10-15 minutes. Surface-decontaminate all materials with 75% ethanol before transferring to a biosafety cabinet. The HepG2 cells used in this study are adherent cells. During cell passaging, aspirate spent medium using a sterile pipette; Wash cells with 5 mL pre-warmed PBS (removal of serum components is critical for effective trypsinization); Completely aspirate PBS and add 1 mL trypsin-EDTA solution (Biological Industries, B03-050-1A); Gently rock dish to ensure even coverage, then aspirate excess trypsin; Incubate at 37°C for ~5 minutes until cells detach (verify under microscope); Gently tap dish to facilitate complete detachment of dispersed cells. Neutralize trypsin activity by adding complete DMEM medium. Based on experimental requirements, prepare appropriate cell dilutions and transfer to fresh culture vessels for continued incubation.

Cell Cryopreservation

Prepare the cryopreservation solution: 90% FBS + 10% DMSO (Sangon Biotech, A100231-0500). Examine cells under an inverted microscope and select healthy and actively growing cultures for cryopreservation. Briefly, follow the same standard passaging procedures: Aspirate spent culture medium; Wash monolayer with pre-warmed 1× PBS; Add 1 mL trypsin-EDTA and incubate at 37°C until detachment (~5 min); Neutralize trypsin with complete growth medium; Transfer cell suspension to a 15 mL centrifuge tube. Centrifuge at 200 × g for 5 minutes at room temperature; Carefully aspirate supernatant without disturbing the cell pellet. Gently resuspend the cell pellet in pre-chilled (4°C) freezing medium; Transfer cell suspension into sterile 2 mL cryovials; Place vials in a controlled-rate freezing container; Store at -80°C or transferring to liquid nitrogen storage

Cell Counting

Follow the same steps as in cell passaging: remove the culture medium from the cells to be counted, wash with pre-warmed PBS, digest with trypsin, neutralize with complete DMEM medium. Gently pipette to achieve single-cell suspension, and dilute to appropriate concentration for counting. Clean the hemocytometer and coverslip thoroughly with lens paper. Using a calibrated 10 µL pipette, load exactly 10 µL of cell suspension onto the hemocytometer chamber. Count the total number of cells in eight large squares of the hemocytometer (ideally 30-100 cells per square), calculate average cell count per square, and multiply by the dilution factor. Finally, multiply by 10,000 to obtain the number of cells per milliliter of cell suspension. Counting rule: include cells touching top and left borders, exclude cells touching bottom and right borders.

Cell Proliferation

Wash cells twice with PBS to completely remove residual DMEM, then fully digest cells with trypsin. Perform cell counting to determine cell density (cells/mL), and dilute to a final concentration of 50,000 cells/mL (5×10⁴ cells/mL). Prepare four 12-well plates, adding 1 mL of cell suspension to each well. Gently shake to mix, then incubate overnight at 37°C in 5% CO₂ to allow complete cell adhesion. After cell adhesion is achieved, prepare GO-Y030 (GlpBio, 917813-62-8) working solutions in DMEM at concentrations of 0 µM (control), 0.25 µM, 0.5 µM, and 0.75 µM. For the control group, add an equivalent volume of DMSO (final concentration < 0.1%). Aspirate the overnight culture medium from all wells, then replace with freshly prepared drug-containing medium according to the concentration gradient. At 0 h, 24 h, 48 h, and 72 h post-treatment: Remove one plate at each time point; Perform cell counting from three replicate wells; Record the average cell number.

Crystal Violet Staining

Wash the test cells with PBS to remove DMEM, then fully digest them with 0.25% trypsin. Perform cell counting using a hemocytometer to determine the cell density (cells/mL), and dilute the cells to a density of 50,000 cells/mL (5×10⁴ cells/mL). Prepare one 12-well plate, and add 1 mL of cell suspension to each well (5×10⁴ cells/well). Gently rock the plate to ensure uniform distribution, then incubate the cells overnight at 37°C in 5% CO₂ to allow complete adhesion. 

After the cells have adhered, prepare GO-Y030 working solutions in DMEM at concentrations of 0 µM (vehicle control), 0.25 µM, 0.5 µM, and 0.75 µM. For the control group, add an equivalent volume of DMSO (final concentration < 0.1%). Carefully remove the DMEM from the 12-well plate that has been cultured overnight, and add the freshly prepared drug-containing medium according to the concentration gradient. Continue to incubate the cells in a 37°C, 5% CO₂ incubator for 72 h (3 days). 

After incubation, remove the 12-well plate from the incubator and gently wash each well twice with 1× PBS. Add 1 mL of ice-cold methanol (Sangon Biotech, A506806-0005) to each well for cell fixation. Place the plate on an orbital shaker (100 rpm) and fix the cells for 20 minutes at room temperature. Then, completely remove the methanol and add 1 mL of 1% (w/v) crystal violet (Yubo Biologycal, C0528-25g) staining solution to each well. Stain the cells on the shaker (50 rpm) for 30 minutes at room temperature. Carefully recover the crystal violet solution for proper disposal. Rinse each well gently with 1× PBS until the wash solution becomes colorless. Allow the plate to air-dry completely at room temperature. Finally, acquire high-resolution digital images of the stained 12-well plate using a standardized scanning protocol.

CCK-8 Assay

As shown in the diagram, add 150 μL of PBS to the outermost 36 wells of the 96-well plate to create a humidity barrier, preventing evaporation in the central experimental area (red region) from affecting the final results. Designate the rightmost column of the red region as the blank control group (Blank), and add 100 μL of complete medium without cells to each well of the blank group using an 8-channel pipette.

Wash the test cells with PBS to remove residual DMEM, then fully digest with 0.25% trypsin-EDTA. Perform cell counting using a hemocytometer to determine the cell density (cells/mL), and dilute the suspension to 50,000 cells/mL (5×10⁴ cells/mL). Using a multichannel pipette, add 100 μL of cell suspension (containing 5,000 cells) to each well of the left 9 columns in the red region.

After incubating the cells for 24 h to allow attachment, prepare GO-Y030 using serial dilution. First, prepare 700 μL of the drug at twice the maximum concentration. Add 100 μL of this solution to the first column to the left of the blank control group. Mix the solution thoroughly using the multichannel pipette. Then, transfer 100 μL of the mixture to the next column and mix thoroughly to reduce the concentration by half. Repeat this process for the remaining columns, with the last column being the untreated control group for comparison. This process creates eight drug treatment groups, with each adjacent column having a concentration difference of two-fold. After drug addition, return the cells to the incubator for further incubation.

After 48 h of drug treatment, replace medium in all wells with 100 μL DMEM containing 10% CCK-8 reagent (GlpBio, GK10001), protecting from light during all subsequent steps. Incubate the 96-well plate in the incubator at 37°C for 1-2 h in the dark. Measure the absorbance at 450 nm using a microplate reader. Calculate the relative cell viability (%) using the formula:

(1)  

Input the relative cell viability and corresponding concentrations into GraphPad Prism 8.0 software. Perform nonlinear regression (X-Y) to generate dose-response curves, from which the software will automatically calculate the IC50 value (the drug concentration that inhibits 50% of cell activity) and the associated standard error.

Cell Cycle Analysis

HepG2 cells were harvested by trypsinization, washed twice with PBS containing 5% FBS, fixed in 70% ethanol followed by staining with 20 μg/ml propidium iodide containing 20 μg/ml RNase (DNase free). Stained cells were analyzed by flow cytometry.

Mouse Xenograft Experiments 

All animal experiments were approved by the Institutional Animal Care and Use Committee (IACUC) of the South China University of Technology (AEC number, 2024061), following the guidelines of the Animal Research Ethics Committee. Three-week-old male nude mice were purchased from SLACCAS. For xenograft experiments, 4×10⁶ HepG2 cells were suspended in sterile PBS and subcutaneously injected into the right flank of each mouse. When tumors reached approximately 100 mm³ in size, mice were randomly assigned to different treatment groups. GO-Y030 (purchased from GLPBIO) was prepared as a solution in DMSO and further diluted in sterile PBS for injection. Mice received intraperitoneal injections of GO-Y030 at doses of 25, 50, or 100 mg/kg every 3 days, starting one week after tumor cell inoculation. The control group received equivalent volume of vehicle solution (DMSO in PBS). Tumor growth was monitored every other day using digital calipers. Tumor volume was calculated using the formula: Tumor volume (mm³) = length (mm) × width (mm) × depth (mm) × 0.52.

Hematoxylin and eosin (H&E) Staining

H&E staining was performed according to standard protocols. Briefly, paraffin-embedded tissue sections were: dewaxed twice in xylene (5 minutes each, rehydrated through a graded ethanol series (100%, 95%, and 75% for 5 minutes each), rinsed in distilled water. Nuclear staining was achieved by immersing sections in hematoxylin for 2 minutes, followed by differentiation in 1% acid alcohol for 5-10 seconds and bluing in running tap water for 5 minutes. Cytoplasmic counterstaining was performed using 0.5% alcohol soluble eosin for 5-10 minutes. After staining, sections were quickly dehydrated through a graded ethanol series (95%, and 100% for 10 seconds each), cleared in xylene (two times, 5 minutes each), and mounted with neutral balsam for microscopic examination.

Immunohistochemistry (IHC) Analysis

Immunohistochemistry was performed following standard procedures. Tissue samples were first dewaxed using xylene and sequentially rehydrated through a graded ethanol series. The tissue sections were repaired with citrate and then blocked with 0.3% hydrogen peroxide for 10 min and then in normal goat serum for 15 min. Primary antibody incubation was carried out at room temperature for 3-6 h (or overnight at 4°C for enhanced sensitivity). After thorough washing, sections were incubated with the appropriate secondary antibody for 25 minutes. DAB chromogen solution was then applied for color development according to the manufacturer’s instructions. Finally, sections were dehydrated through an ascending ethanol series, cleared in xylene, and mounted with neutral balsam. All stained sections were examined and photographed under a light microscope.

Western Blotting Analysis 

Mouse tumor tissues were minced and lysed in RIPA buffer (50 mM Tris-Cl, pH 8.0, 150 mM NaCl, 5 mM EDTA, 0.1% SDS, 1% NP-40) supplemented with protease inhibitor cocktails (5056489001, Roche) for 45 min. Equal amounts of proteins were then fractionated by SDS-PAGE, followed by transfer to NC membrane. The membrane was blocked with 5% milk for 1 h, followed by incubation with primary antibodies against P21, P53, or β-actin (Santa Cruz) for 2 h at room temperature. After washing 3 times with washing buffer TBST, the membrane was incubated with HRP-conjugated anti-rabbit or anti-mouse secondary antibody (Proteintech) for 1 h, followed by washing for three times. The signal was detected using Western ECL Substrate (Bio-Rad).

Data Analysis

All quantitative data in the paper were obtained from three independent experiments and are presented as mean ± standard error of the mean (SEM). Statistical analysis was performed using GraphPad Prism 8.0 software, employing one-way ANOVA to determine P-values. A P-value of less than 0.05 was considered statistically significant (denoted by “*”).

Results

Curcumin has been widely recognized for its antitumor properties; however, its clinical application is limited due to drawbacks such as low bioavailability and poor stability. To address these limitations, researchers have synthesized structural analogs of curcumin (Figure 1A), including GO-Y030 (Figure 1B), which exhibits enhanced biological activity. However, the precise role of GO-Y030 in hepatocellular carcinoma (HCC) remains unclear. In this study, we investigated the antitumor effects of GO-Y030 in human HCC HepG2 cell line and explored its underlying mechanisms. Based on previous studies, we treated HepG2 cell lines with GO-Y030 at concentrations of 0.25, 0.5, and 0.75 μM for 0, 24, 48, and 72 h, respectively. Using a hemocytometer, we quantified cell proliferation after treating HepG2 cells with GO-Y030. The results demonstrated that GO-Y030 inhibited cell proliferation in a dose- and time-dependent manner in HepG2 cell lines, with statistical significance (P < 0.05) (Figure 2A). To further confirm these findings, we performed crystal violet staining after removing the culture medium and washing with PBS. Consistently, GO-Y030 treatment reduced the number of viable cells in a concentration-dependent manner (Figure 2B).

Subsequently, to determine the relationship more precisely between GO-Y030 concentration and its inhibitory effect on cell proliferation, we treated HepG2 cells with varying GO-Y030 concentrations for 48 h and assessed viability using the CCK-8 assay. Results showed a gradual decrease in relative cell viability in HepG2 liver cancer cell lines as the concentration of GO-Y030 increased (Figure 3). Analysis using GraphPad Prism 8.0 software revealed that the IC50 of GO-Y030 was approximately 0.46 μM in HepG2 cells, respectively (Figure 4). Guo et al. reported that the IC50 of curcumin on HepG2 cells is approximately 20 μM⁵. Therefore, we estimate that the water solubility and bioavailability of GO-Y030 are approximately 40 times higher than those of curcumin. These results indicate that, compared with curcumin, GO-Y030 is able to more effectively inhibit the proliferative activity of HepG2 liver cancer cells.

The above in vitro results indicate that GO-Y030 significantly inhibits the proliferation of hepatocellular carcinoma cells. To further evaluate the antitumor activity of GO-Y030 in vivo, we established a HepG2 xenograft tumor model in mice by subcutaneous injection and treated the mice with GO-Y030. The recorded tumor growth curves showed that GO-Y030 significantly inhibited the tumor growth of the HepG2 xenografts in a dose-dependent manner (Figure 5A). At the experimental endpoint, the mice were sacrificed and the tumors were excised and photographed (Figure 5B). The results showed that GO-Y030 treatment significantly inhibited tumor growth in a concentration-dependent manner; in the high-dose treatment group, complete tumor growth inhibition was observed in one mouse (Figure 5B). Statistical analysis of tumor weights yielded results consistent with the tumor growth curves and tumor photographs, showing significant differences (Figure 5C).

P53 is a well-known tumor suppressor protein, and its mediated signaling pathways, such as the P21 pathway, are widely involved in tumor regulation. To investigate whether the in vitro and in vivo antitumor effects of GO-Y030 depend on the P53 pathway, we performed Western blot analysis on the protein lysates extracted from tumor tissues. The results showed that GO-Y030 treatment significantly upregulated the protein levels of the tumor suppressor P53 and its downstream target P21 (Figure 6). Consistently, immunohistochemical (IHC) staining of tumor tissues revealed that the protein expression levels of both P53 and P21 were increased in the GO-Y030-treated group compared to the control group (Figure 7). These findings suggest that the upregulation of P53 expression may be involved in the antitumor mechanism of GO-Y030. Taken together, these data indicate that GO-Y030 may inhibit the growth of hepatocellular carcinoma by regulating the P53 signaling pathway.

Discussion

Liver cancer remains a significant public health concern in China, ranking as the fourth most prevalent cancer and the second leading cause of cancer-related mortality¹. In 2020, 367,657 Chinese people were diagnosed with liver cancer, accounting for 7.6% of all cancer cases²². Conventional treatments like chemotherapy and radiotherapy frequently demonstrate limited therapeutic efficacy while causing adverse effects including alopecia, emesis, and diarrhea¹⁰. These limitations underscore the urgent need for developing more effective and less toxic therapeutic agents.

Bioactive compounds (phytochemicals) have emerged as promising candidates exhibiting both growth-suppressive and chemopreventive activities against various malignancies⁷. Curcumin, a well-studied polyphenol, demonstrates potent antioxidant and anti-inflammatory properties^7’23. Curcumin has also been demonstrated to protect against carcinogenesis and aid in preventing the formation and development of different cancer types. In animal tumor models, curcumin has been observed to inhibit both angiogenesis and metastasis^{7’24’25’10’26’27’28’29’30}. However, due to its low bioavailability, curcumin is not a suitable therapeutic agent for cancer therapy. Analogues of curcumin exhibit increased anticancer potency, among which GO-Y030 has been shown to be the most potent in suppressing tumor growth in many cancer cell types^31’32. 

This research demonstrates that GO-Y030 exhibits a remarkable inhibitory effect on the cell viability/proliferation of human HepG2 liver cancer cells at a concentration over 0.25 μM. Therefore, it will be of interest to evaluate the inhibitory efficacy of curcumin analogues, especially GO-Y030, in tumor models both in vivo and in vivo in the future. Further, more studies are needed to evaluate the effect of GO-Y030 in combination therapy with current clinical chemotherapy agents as well as immunotherapy strategies.

This research demonstrated that the new curcumin analogue, GO-Y030, exhibits strong potential in the inhibition of cell proliferation and the induction of apoptosis in human HepG2 liver cancer cell lines. These results position GO-Y030 as a promising candidate for clinical development in liver cancer treatment and prevention, meriting further comprehensive evaluation.

Acknowledgment

We would like to thank our supervisor Caixia Suo from Guangzhou First People’s Hospital for her guidance, support and help throughout these experiments, providing insightful comments and helping us with the experiments, especially the animal experiment. Without her kind support and supervision, we could not have achieved our results. Thanks also for the resources provided; they are the footstone of our research. Meanwhile, we would like to thank Kaixiang Fan from the South China University of Technology for his help with the experimental operation and data analysis.

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