Novel compounds of Taiwanese green propolis induce apoptosis of human glioblastoma cells by daylight photodynamic action
Abstract
Background
Glioblastoma, an aggressive brain cancer, has limited treatment options and poor prognosis. Taiwanese green propolis, known for its tumor-inhibitory properties, shows promise when combined with photodynamic therapy (PDT), a targeted, low-toxicity treatment. This study investigated a novel Taiwanese green propolis-based compound for inducing apoptosis in glioblastoma cells and its synergistic potential with daylight PDT.
Methods
Ethanol extracts of green propolis, wheatgrass, and mulberry leaves were combined and analyzed using High-Performance Liquid Chromatography (HPLC). Apoptosis induction in U87 glioblastoma cells was assessed via the MTT assay following treatment with the compound alone and in combination with daylight PDT at 570 nm.
Results
We identified Artepillin C as the main active component in the compound by HPLC, which significantly induced apoptosis in glioblastoma cells. Combined with daylight PDT, it demonstrated enhanced efficacy, with cell viability reduced from 95.2% at 0.25 µL to 11.3% at 8 µL of the compound extract. The EC50 decreased, indicating greater apoptotic activity compared to the extract alone.
Conclusion
This study provides the first in vitro evidence of synergistic anti-tumor effects of a Taiwanese green propolis-based compound daylight PDT (GPDT), highlighting a promising novel therapeutic approach that warrants further clinical investigation.
PLAIN LANGUAGE SUMMARY
Glioblastoma is a fast-growing and deadly brain cancer. It is hard to treat, and most patients do not live long. In our study, we tested new compounds made from Taiwanese green propolis, wheatgrass, and mulberry leaves. These compounds are known to help fight cancer. We also used a method called daylight photodynamic therapy (PDT), which uses light to safely activate the treatment.
Our results showed that the new compounds can destroy cancer cells. When combined with daylight PDT, they worked even better. This is the first study to show that green propolis-based compound and daylight PDT (GDPT) can work together to destroy cancer cells. While the results are new, more research is needed to make sure it is safe and can help patients.
ARTICLE HIGHLIGHTS
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Taiwanese green propolis has demonstrated tumor-inhibitory properties, offering potential for novel cancer treatments.
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Daylight photodynamic therapy (PDT) is a low-toxicity, light-based treatment that can enhance the effects of other therapies.
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A novel compound was developed by combining ethanol extracts of green propolis, wheatgrass, and mulberry leaves (GP-WM extract).
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High-Performance Liquid Chromatography (HPLC) was used to identify the main active component, Artepillin C.
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Human glioblastoma cells (U87) were treated with the compound alone and in combination with daylight PDT at 570 nm for 24 hours.
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A significant dose-dependent reduction in cell viability was observed with the GP-WM extract combined with daylight PDT. At a dose of 0.25 µL, cell viability decreased from 100% to 95.2%. The reduction further decreased to 16.9% at 4 µL and to 11.3% at 8 µL.
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When combined with daylight PDT, the compound demonstrated enhanced tumor-suppressive activity, reducing the EC50 value.
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This study provides the first in vitro evidence of the synergistic anti-tumor effects of GPDT – Taiwanese green-propolis-based compound combined with daylight PDT.
1. Introduction
Cancer remains a leading cause of morbidity and mortality worldwide, with glioblastomas being one of the most prevalent, aggressive, and treatment-resistant forms of brain cancer. Despite advancements in surgery, chemotherapy, and radiotherapy, the prognosis for glioblastoma remains poor, with a median survival of less than 12 months [Citation1,Citation2], This underscores the need for continued research and innovation to improve outcomes and develop more effective approaches.
Natural products derived from plants have long been recognized for their therapeutic potential in oncology [Citation3–5], used both as drugs and nutraceuticals to support cancer treatment. Among these, green propolis—a resinous substance produced by bees—exhibits diverse bioactive properties, including antitumour [Citation6,Citation7], antioxidant [Citation8–10], antibacterial [Citation11], and anti-inflammatory [Citation12] effects. With over 300 identified compounds in green propolis, such as flavonoids, fatty acids, phenolic esters, alcohols, and alkaloids [Citation9,Citation13,Citation14]. Of these, flavonoids play an important role in their pharmacological activity [Citation15] by inducing apoptosis in various cancer cell lines, highlighting their potential in cancer therapy. Similarly, wheatgrass (Triticum aestivum) has shown antitumor properties, inhibiting various cancers [Citation16], including breast [Citation17], oral squamous cell carcinoma [Citation18], and cervical cancers [Citation19]. Ethanol extracts of wheatgrass have also been effective in suppressing colorectal cancer in mice [Citation20], likely due to sitosterol, which inhibits the proliferation of cancer cells and induces apoptosis [Citation21,Citation22]. Additionally, mulberry leaves also contribute to cancer inhibition by inducing mitophagy in lung cancer cells [Citation23].
Complementing these natural therapies, photodynamic therapy (PDT) has emerged as a promising anticancer treatment. PDT employs photosensitisers and light absorption to generate reactive oxygen species (ROS) through photochemical reactions, inducing oxidative stress and apoptosis in tumor cells () [Citation24]. Recent advancements, such as daylight PDT, have gained attention for their practicability and noninvasive nature, utilizing natural or artificial light sources to broaden clinical applicability and reduce reliance on specialized equipment.
Figure 1. The mechanism of photodynamic therapy (PDT).
Activated by exposure to light source, the photosensitizer (PS) is excited to a singlet state and undergoes intersystem crossing to the excited triplet-state. The triplet-state-excited PS can react in two ways: a Type I reaction, which involves the generation of superoxide anion radical (O2•−), hydrogen peroxide (H2O2), and hydroxyl radical (OH•) by electron transfer to molecular oxygen, and/or a Type II reaction, which involves energy transfer to generate singlet oxygen (1O2). PS: photosensitizer; 1PS*: excited singlet state.3PS*: excited triplet state; ROS: reactive oxygen species.
As shown in , PDT involves the localization of photosensitisers within tumor tissue, which are activated by light of specific wavelengths to produce cytotoxic singlet oxygen, inducing cell apoptosis [Citation25–27]. PDT is often combined with drugs to produce synergistic effects, reducing the required photosensitizer dosage, minimizing toxicity to normal cells, and enhancing therapeutic efficacy [Citation28,Citation29]. The photosensitizer plays a pivotal role in initiating this chain of reactions, with natural chlorophyll derivatives demonstrating effective ROS production [Citation30,Citation31] and highlighting their potential as efficient photosensitisers [Citation32]. Consequently, the combined application of daylight PDT and natural products has gained interest for its potential in cancer therapy.
This study investigates the synergistic effects of a novel green propolis-based extract combined with daylight photodynamic therapy (PDT) on glioblastoma cells, leveraging the tumor-inhibitory properties of green propolis and herbal chlorophyll derivatives. A novel herbal composition was examined, consisting of chlorophyll derivatives from ethanol extract of green propolis, wheatgrass, and mulberry leaves. This study evaluated this composition’s ability to induce apoptosis in human glioblastoma cells and its enhanced efficacy when applied alongside daylight PDT.
2. Materials and methods
2.1. Chemicals
Green propolis was sourced from beehives managed by Zhicheng Bee Farm (Taichung City, Wufeng District, Taiwan) and Mingyu Bee Farm (Taichung City, Waipu District, Taiwan). Wheatgrass was cultivated from the greenhouse of Fang-Gwann Biotechnology Co., Ltd. (Nantou County, Mingjian Township, Taiwan), while mulberry leaves were obtained from the Quanming Ecological Education Sericulture Farm (Miaoli County, Shitan Township, Taiwan).
2.2. Cell lines and culture conditions
The human glioblastoma cell line U87 (BCRC 60360) was obtained from the Bioresource Collection and Research Center (BCRC) of the Food Industry Research and Development Institute (FIRDI) in Hsinchu City, Taiwan. U87 cells were cultured in a 10-cm Petri dish containing Dulbecco’s Modified Eagle’s Medium (DMEM) (Gibco, Cat. No. 12100-038) supplemented with 10% fetal bovine serum (FBS) and 1% penicillin–streptomycin. The cells were cultured in an incubator at 37 °C and 5% CO2, and the medium was replaced every two to three days. Cell passaging was performed when the cultures reached 80% to 90% confluence.
2.3. Preparation of the extract compound
The extract compound was prepared based on the weight ratio of active compounds, specifically ethanol extracts of green propolis, wheatgrass, and mulberry leaves. Detailed extraction methods and preparation processes are described in the study for transparency and reproducibility.
2.3.1. Green propolis (GP) extraction
Green propolis was mixed with 95% ethanol at a weight ratio of 1:3 and subjected to ultrasonication at 30 °C to 50 °C for 1 hour, followed by filtration. The ethanol mixing-ultrasonication-filtration step was repeated three times, and all filtrates were vacuum-concentrated to produce the ethanol extract of the green propolis. The resulting product was mixed with propylene glycol at a 1:1 ratio, ultrasonicated for 10 minutes, and vacuum-concentrated at 55 °C to 65 °C to yield a propylene glycol solution of green propolis extract. This solution was then mixed with triglycerides at a weight ratio of 2:1, ultrasonicated for 10 minutes, and separated using a thistle funnel. The lower layer was collected to obtain a dewaxed propylene glycol solution containing green propolis extract (GP extract).
2.3.2. Wheatgrass and mulberry leaf extraction
Dried wheatgrass (100 g) and dried mulberry leaves (100 g) were each mixed with 200 mL of 95% ethanol, ultrasonicated at 30 °C to 50 °C for 30 minutes, and filtered to collect their respective ethanol extracts. Both extracts were then mixed at a ratio of 1:1 and left standing at 25 °C for 36 hours. The mixture was filtered, and the resulting filtrate was then mixed with propylene glycol at a 1:1 ratio. Ethanol was removed by vacuum concentration, producing a propylene glycol solution containing wheatgrass extract and mulberry leaf extract (WM extract).
2.3.3. GP-WM extract
The GP extract and the WM extract were combined at a ratio of 1:1 to obtain a composite extract referred to as the GP-WM extract. Concentrations were represented as weight/weight ratios and tested in varying volumes (0.25, 0.5, 1, 2, 4, and 8 µL) in the study.
2.4. High-performance liquid chromatography (HPLC) analysis
The GP-WM extract prepared in this study was analyzed using high-performance liquid chromatography (HPLC) at the Food Industry Research and Development Institute (FIRDI), Taiwan. The operating parameters and conditions for performing HPLC are detailed in .
Table 1. The operating parameters and conditions for performing HPLC.
2.5. Cell viability assay
Cell viability was assessed using the MTT assay. U87 cells were placed in a 96-well culture plate at a density of 1 × 104 cells/well and incubated with 100 μL of DMEM at 37 °C and 5% CO2 for 24 hours. Subsequently, the cells were treated with varying concentrations (0.25, 0.5, 1, 2, 4, and 8 µL) of one of the GP extracts, WM extract, or the GP-WM extract for 24 hours. Untreated cell cultures served as the control group. Following treatment, all cell cultures were exposed to daylight PDT at a wavelength of 570 nm using a fluorescent laser light-emitting diode (LED) lamp for 24 hours.
After the PDT treatment, the medium in each well was removed, and 5 mg/mL of MTT solution was added. The cells were then incubated at 37 °C and 5% CO2 for an additional 24 hours. The MTT solution was then removed, and the samples were washed twice with PBS (pH 7.4). Finally, 50 µL of DMSO was added to each well, and the resulting reaction mixture was measured for absorbance at a wavelength of 570 nm (OD570) using an ELISA reader (BioTek, Cat. No. Synergy HTX). The median effective dose (EC50) was determined from the linear portion of the plotted dose-response curve.
2.6. Statistical analysis
Statistical analyses were performed using GraphPad Prism 9 software. Data were presented as mean ± SE for proportional viability (%) and EC50 values. p-values were calculated using one-way ANOVA followed by post hoc tests. Post hoc tests were conducted only when the F-statistics indicated P < 0.05 and no significant inhomogeneity of variance was detected. ANOVA was also used for between-group comparisons (with or without PDT treatment) of dose-response proportional viability of the same extract at a concentration of 8 μL. A significance threshold of P < 0.05 was applied to evaluate the statistical significance of the results.
3. Results
3.1. Phytochemical analysis of the extract compound by HPLC
To identify the components in the extracts, HPLC was performed. The HPLC spectrum of the GP-WM extract is shown in . Two prominent peaks (peaks a1 and a2) were observed during the 20-minute retention period. Based on comparison with the standard references, the a1 and a2 peaks were identified as Artepillin C, indicating that this compound is the primary constituent of the GP-WM extract. Artepillin C, a unique active substance found in Taiwanese green propolis [Citation33], has been shown to inhibit tumor cell proliferation and metastasis [Citation34]. This study focused on investigating the apoptosis-inducing effects of the GP-WM extract.
Figure 2. HPLC spectrum of the GP-WM extract.
Separation of standard authentic compounds of the GP–WM extract by HPLC. Peaks: a1 and a2 identified as compounds related to Artepillin C. The conditions of separation are listed in .
3.2. Evaluation of the effects of the extracts on the induction of U87 cell apoptosis
We evaluated the inhibitory effects of the GP extract, WM extract, and GP-WM extract on U87 cell apoptosis in the absence of daylight PDT. Results indicated that the percentage of viable cells treated with the GP-WM extract was lower compared to the other two extracts and significantly lower than those treated with the WM extract at varying concentrations (0.25, 0.5, 1, 2, 4, and 8 µL) (). Furthermore, a dose-dependent effect of the GP-WM extract was observed on the percentage of viable cells.
Figure 3. Effect of GP, WM and GP-WM extract on the viability of human Glioblastoma U87 cells.
The cells were treated with various concentrations (0.25, 0.5, 1, 2, 4, and 8 µL) of GP, WM and the GP-WM extract for 24 h and subsequent cell viability was measured via MTT assay. The data are presented in terms of proportional viability (%). Results represent the mean ± SE of three independent experiments. Statistical analysis was performed using one-way ANOVA followed by post hoc tests, with a significance threshold set at P < 0.05 to determine the statistical significance of the results.
To further relate the inhibitory effects to proliferation and cell viability, EC50 values were determined through sigmoidal curve fitting of the calculated growth rates. Among the tested extracts, the GP-WM extract exhibited the lowest EC50 values in U87 cells at 6.581 µL.
Dose-dependent effects on U87 cell viability were observed: 0.25 µL of the GP-WM extract reduced viability from 100% to 94.8%; 0.5 µL reduced viability to 68.7%; 1 µL reduced viability to 54.8%; 2 µL reduced viability to 42.8%; 4 µL reduced viability to 27.2%; and 8 µL reduced viability to 14.6%. These results indicate that the GP-WM extract effectively inhibited the growth of human glioblastoma cells in a dose-dependent manner.
3.3. Evaluation of the effects of the extracts combined with daylight PDT on the induction of apoptosis in U87 cells
The effects of the extracts combined with photodynamic therapy (PDT) were analyzed using the MTT assay in U87 cells. The efficacy of the GP extract, WM extract, and GP-WM extract improved after the combined photodynamic treatment (). Notably, the GP-WM extract demonstrated significantly greater U87 cell growth inhibition compared to the GP extract and WM extract at the same concentration. The EC50 of the GP-WM extract decreased from 6.581 µL (alone) to 3.5 µL when combined with PDT, indicating enhanced efficacy.
Figure 4. Effect of GP, WM and GP-WM extract on the viability of human Glioblastoma U87 cells combined with daylight PDT.
(A) The cells were treated with various concentrations (0.25, 0.5, 1, 2, 4, and 8 µL) of GP, WM and the GP-WM extract for 24 h in combination with daylight PDT (wavelength 570 nm) and subsequent cell viability was measured via MTT assay. The data are presented in terms of proportional viability (%). Results represent the mean ± SE of three independent experiments. (B) The percentages of viable cells treated with the GP extract, the WM extract, or the GP-WM extract with or without daylight PDT at the same concentration (8 μL) were compared. Statistical analysis was performed using one-way ANOVA followed by post hoc tests, with a significance threshold set at P < 0.05 to determine the statistical significance of the results.
A significant dose-dependent reduction in cell viability was observed with the GP-WM extract combined with daylight PDT. At a dose of 0.25 µL, cell viability decreased from 100% to 95.2%. The reduction further decreased to 16.9% at 4 µL and to 11.3% at 8 µL.
Additionally, we compared the ability of the GP-WM extract to induce apoptosis with or without daylight PDT at the same concentration (8 μl). As shown in , the combination of the GP-WM extract and daylight PDT induced cell apoptosis more efficiently than the extract alone. These findings indicate that the GP-WM extract exhibits significant efficacy in inducing apoptosis of U87 cells, especially when combined with daylight PDT.
4. Discussion
By 2030, the global incidence of cancer is expected to be 26 million cases annually [Citation35]. Despite advances in treatments, conventional treatments often face limitations such as severe side effects, drug resistance, and high costs [Citation36]. Therefore, novel and alternative therapies, particularly those derived from natural products, hold promise for cancer treatments [Citation37,Citation38].
This study synthesized and evaluated the apoptotic effects of a novel GP-WM extract compound, comprising ethanol extracts from green propolis, wheatgrass, and mulberry leaves, which effectively inhibited the growth and induced apoptosis of human glioblastoma cells. Our results indicated that flavonoids in green propolis, particularly Artepillin C, are likely contributors to the antitumour effects of green propolis [Citation39], while chlorophyll derivatives may enhance the effect of PDT [Citation40,Citation41], and we suggest that active compounds such as sitosterol in wheatgrass [Citation21,Citation22], and flavonoids and alkaloids [Citation23] in mulberry leaves further enhance this effect.
Additionally, chlorophyll derivatives in these extracts enhance the efficacy of photodynamic therapy (PDT) [Citation40,Citation41]. Daylight PDT, which selectively targets malignant cells using photosensitisers, demonstrates synergistic effects with chlorophyll-containing compounds. Combining daylight PDT with green propolis has been shown to increase cytotoxicity and induce apoptosis in cervical cancer cells [Citation42,Citation43], and enhance immune response [Citation44]. Nevertheless, further studies are needed to identify the specific bioactive compounds responsible for these effects.
Our results demonstrated that the combination of daylight PDT with the GP-WM extract significantly enhanced the inhibitory effect on human glioblastoma cells in vitro. However, in vivo validation is essential to establish the clinical potential and applicability as a novel cancer treatment. Using U87 cells, we demonstrated the compound’s efficacy both alone and in combination with daylight PDT. While these findings are promising, further research involving additional cell lines and models is required to confirm broader applicability. Future studies will focus on standardizing extract preparation, evaluating safety in preclinical and clinical settings, and comparing the compound’s effects with standard glioblastoma treatments, such as chemotherapy and radiotherapy, to assess its therapeutic potential.
This is the first study to demonstrate the apoptotic effects of this novel compound of Taiwanese Green Propolis in combination with PDT. As in , we outline the conceptual mechanism of GP-WM in generating reactive oxygen species (ROS) and inducing apoptosis in U87 cells via daylight PDT. The figure highlights potential pathways involved, serving as a basis for future experimental studies to validate these mechanisms.
Figure 5. Conceptual mechanism of action of GP-WM in inducing apoptosis through daylight PDT.
GP-WM, activated by specific light wavelengths (570 nm) within the visible spectrum (400–700 nm), functions as a photosensitizer to produce reactive oxygen species (ROS) or free radicals through daylight photodynamic therapy (PDT). These ROS trigger apoptosis in U87 cells, ultimately causing cell destruction. The figure illustrates the key steps in this mechanism, emphasizing the critical roles of light activation and oxidative stress in achieving efficacy.
In conclusion, our study demonstrated that ethanol extract compounds derived from green propolis, wheatgrass, and mulberry leaves exhibit inhibitory effects on human glioblastoma cells in vitro. The combination with daylight photodynamic (PDT) significantly enhanced these effects, highlighting a novel synergistic interaction. While this study provides the first in vitro evidence of its efficacy, it serves as a foundational step for future investigations and potential contributions to novel therapeutic applications in oncology.
Author contributions
Conceptualization, YKC and D T-H C; methodology, YKC and D T-H C; software and formal analysis, D T-H C; writing—original draft preparation, D T-H C; writing—review and editing, D T-H C, SYH, TCL, YKC. YKC and D T-H C are the patent holders for the invention derived from this study, which has been granted in Taiwan (Patent No: I806696) and the United Kingdom (GB2305047.9). SYH and TCL were responsible solely for drafting and revising the manuscript and did not contribute to the development or intellectual property aspects of the invention. All authors have read and agreed to the published version of the manuscript
Disclosure statement
The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. YKC and D T-H C declare that they are the patent holders of the invention based on this study, with patents granted in Taiwan (No: I806696) and the United Kingdom (GB2305047.9). SYH and TCL were involved exclusively in the manuscript’s preparation and do not claim any ownership, financial interest, or intellectual property rights related to the patent.
Additional information
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References
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