Cerbera odollam fruit extracts enhance anti-cancer activity of sorafenib in HCT116 and HepG2 cells.
10.1016/j.chmed.2024.11.007
- Author:
Supawadee PARHIRA
1
;
Orakot SIMANURAK
2
;
Khemmachat PANSOOKSAN
3
;
Julintorn SOMRAN
4
;
Apirath WANGTEERAPRASERT
5
;
Zhihong JIANG
6
;
Liping BAI
6
;
Pranee NANGNGAM
7
;
Dumrongsak PEKTHONG
3
;
Piyarat SRISAWANG
3
Author Information
1. Department of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok 65000, Thailand.
2. Department of Physiology, Faculty of Medical Science, Naresuan University, Phitsanulok 65000, Thailand.
3. Center of Excellence for Innovation in Chemistry, Naresuan University, Phitsanulok 65000, Thailand.
4. Department of Pathology, Faculty of Medicine, Naresuan University, Phitsanulok 65000, Thailand.
5. Department of Medicine, Faculty of Medicine, Naresuan University, Phitsanulok 65000, Thailand.
6. State Key Laboratory of Quality Research in Chinese Medicine, Guangdong-Hong Kong-Macao Joint Laboratory of Respiratory Infectious Disease, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau 999078, China.
7. Department of Biology, Faculty of Science, Naresuan University, Phitsanulok 65000, Thailand.
- Publication Type:Journal Article
- Keywords:
Cerbera odollam Gaertn.;
HCT116;
HepG2;
apoptosis;
reactive oxygen species;
sorafenib
- From:
Chinese Herbal Medicines
2025;17(1):108-126
- CountryChina
- Language:English
-
Abstract:
OBJECTIVE:While higher therapeutic doses of toxic cardiac glycosides derived from Cerbera odollam are frequently employed in cases of suicide or homicide, ongoing research is investigating the potential anticancer properties of low-concentration extracts obtained from the fruits of C. odollam. The present study aimed to determine the enhanced anticancer effects and minimize potential side effects of combining extracts from C. odollam fruits from Thailand with sorafenib against HCT116 and HepG2 cells.
METHODS:The dried powder of fresh green fruits of C. odollam was fractionated, and its phytochemical contents, including total cardiac glycosides, phenolics, flavonoids, and triterpenoids, were quantified. The cytotoxic effects of these fractions were evaluated against HCT116 and HepG2 cells using the MTT assay. The fractions showing the most significant response in HCT116 and HepG2 cells were subsequently combined with sorafenib to examine their synergistic effects. Apoptosis induction, cell cycle progression, and mitochondrial membrane potential (MMP) were then assessed. The underlying mechanism of the apoptotic effect was further investigated by analyzing reactive oxygen species (ROS) generation and the expression levels of antioxidant proteins.
RESULTS:Phytochemical analysis showed that C. odollam-ethyl acetate fraction (COEtOAc) was rich in cardiac glycosides, phenolics, and flavonoids, while the dichloromethane fraction (CODCM) contained high levels of triterpenoids and saponins. Following 24 h treatment, HCT116 showed the most significant response to COEtOAc, while HepG2 responded well to CODCM with IC50 values of (42.04 ± 16.94) μg/mL and (123.75 ± 14.21) μg/mL, respectively. Consequently, COEtOAc (20 μg/mL) or CODCM (30 μg/mL), both administered at sub-IC50 concentrations, were combined with sorafenib at 6 μmol/L for HCT116 cells and 2 μmol/L for HepG2 cells, incubated for 24 h. This combination resulted in a significant suppression in cell viability by approximately 50%. The combination of treatments markedly enhanced apoptosis, diminished MMP, and triggered G0/G1 phase cell cycle arrest compared to the effects of each treatment administered individually. Concurrently, increased formation of ROS and decreased expression of the antioxidant enzymes superoxide dismutase 2 and catalase supported the proposed mechanism of apoptosis induction by the combination treatment. Importantly, the anticancer effect demonstrated a specific targeted action with a favorable safety profile, as evidenced by HFF-1 cells displaying IC50 values 2-3 times higher than those of the cancer cells.
CONCLUSION:Utilizing sub-IC50 concentrations of COEtOAc or CODCM in combination with sorafenib can enhance targeted anticancer effects beyond those achieved with single-agent treatments, while mitigating opposing side effects. Future research will focus on extracting and characterizing active constituents, especially cardiac glycosides, to enhance the therapeutic potential of anticancer compounds derived from toxic plants.
