Synergistic anti-tumorigenic effect of diosmetin in combination with 5-fluorouracil on human colon cancer xenografts in nude mice.

5-Fluorouracil (5-FU) is frequently used to treat colorectal cancer (CRC), but its clinical application is limited by its toxicity. Natural compounds have been combined with chemotherapeutic drugs to reduce chemotherapy-related toxicity. Diosmetin, a natural flavonoid, has demonstrated anticancer effects against CRC. This study investigated diosmetin's potential in combination with 5-FU using a murine model of HCT-116 colon cancer xenografts in nu/nu nude mice. HCT-116 cells were injected into the right flanks of mice, and once tumors reached a size of 50 mm3, the mice were treated with diosmetin (100 mg/kg), 5-FU (30 mg/kg), or a combination of both at two dose levels (100 + 30 mg/kg and 50 + 15 mg/kg) for 4 weeks. Blood and tumors were collected on the final day for further analysis. Mice treated with the higher combination dose exhibited the smallest tumor volume (330.91 ± 88.49 mm3). Biochemistry and histology analysis showed no toxicity or abnormalities in the liver, kidney, and heart with the combination therapy. Immunohistochemistry results revealed a notable reduction in the proliferation marker (Ki67) and inflammation marker (TLR4) in tumors from high-dose combination-treated mice. Moreover, immunofluorescence data indicated increased levels of apoptotic markers (Bax, Caspase-3, p53, p21) and downregulation of anti-apoptotic protein (Bcl-2) in the high-dose combination group. The findings suggest that 100 mg/kg of diosmetin combined with 30 mg/kg 5-FU significantly reduced tumor volume and had a less toxic effect on the heart compared to 5-FU monotherapy.

Enhancing the Anti-Leukemic Potential of Thymoquinone/Sulfobutylether-ß-cyclodextrin (SBE-ß-CD) Inclusion Complexes.

Leukemia, a condition characterized by the abnormal proliferation of blood cells, poses significant challenges in cancer treatment. Thymoquinone (TQ), a bioactive compound derived from black seed, has demonstrated anticancer properties, including telomerase inhibition and the induction of apoptosis. However, TQ's poor solubility and limited bioavailability hinder its clinical application. This study explored the use of Sulfobutylether-ß-cyclodextrin (SBE-ß-CD), a cyclodextrin derivative, to enhance the solubility and stability of TQ for leukemia treatment. SBE-ß-CD offers low hemolytic activity and has been successfully employed in controlled drug release systems. The study investigated the formation of inclusion complexes between TQ and SBE-ß-CD and evaluated their effects on leukemia cell growth and telomerase activity. The results indicated that the TQ/SBE-ß-CD complex exhibited improved solubility and enhanced cytotoxic effects against K-562 leukemia cells compared to TQ alone, suggesting the potential of SBE-ß-CD as a drug delivery system for TQ. The annexin V-FITC assay demonstrated increased apoptosis, while the qPCR quantification assay revealed reduced telomerase activity in leukemia cells treated with TQ/SBE-ß-CD, supporting its anti-leukemic potential. The molecular docking analysis indicated a strong binding affinity between TQ and telomerase. However, further research is needed to optimize the apoptotic effects and minimize necrosis induction. In conclusion, TQ/SBE-ß-CD shows promise as a novel strategy for leukemia treatment by inhibiting telomerase and enhancing the cytotoxic effects of TQ, offering a potential solution to overcome the limitations of TQ's poor solubility and bioavailability.

Characterization of Thymoquinone-Sulfobutylether-ß-Cyclodextrin Inclusion Complex for Anticancer Applications.

Thymoquinone (TQ) is a quinone derived from the black seed Nigella sativa and has been extensively studied in pharmaceutical and nutraceutical research due to its therapeutic potential and pharmacological properties. Although the chemopreventive and potential anticancer effects of TQ have been reported, its limited solubility and poor delivery remain the major limitations. In this study, we aimed to characterize the inclusion complexes of TQ with Sulfobutylether-ß-cyclodextrin (SBE-ß-CD) at four different temperatures (293-318 K). Additionally, we compared the antiproliferative activity of TQ alone to TQ complexed with SBE-ß-CD on six different cancer cell lines, including colon, breast, and liver cancer cells (HCT-116, HT-29, MDA-MB-231, MCF-7, SK-BR-3, and HepG2), using an MTT assay. We calculated the thermodynamic parameters (ΔH, ΔS, and ΔG) using the van't Holf equation. The inclusion complexes were characterized by X-ray diffraction (XRD), Fourier transforms infrared (FT-IR), and molecular dynamics using the PM6 model. Our findings revealed that the solubility of TQ was improved by ≥60 folds, allowing TQ to penetrate completely into the cavity of SBE-ß-CD. The IC50 values of TQ/SBE-ß-CD ranged from 0.1 ± 0.01 µg/mL against SK-BR-3 human breast cancer cells to 1.2 ± 0.16 µg/mL against HCT-116 human colorectal cancer cells, depending on the cell line. In comparison, the IC50 values of TQ alone ranged from 0.2 ± 0.01 µg/mL to 4.7 ± 0.21 µg/mL. Overall, our results suggest that SBE-ß-CD can enhance the anticancer effect of TQ by increasing its solubility and bioavailability and cellular uptake. However, further studies are necessary to fully understand the underlying mechanisms and potential side effects of using SBE-ß-CD as a drug delivery system for TQ.

Effect of monosodium glutamate on serum sex hormones and uterine histology in female rats along with its molecular docking and in-silico toxicity.

Monosodium glutamate (MSG) is commonly used worldwide as a food flavour enhancer by the food industry. The current study investigated the in vivo toxic effects of MSG on the uterus in adult female Sprague Dawley rats and in vitro using MCF-7 and MDA-MB-231 cells, computational toxicity and molecular docking. The average levels of progesterone and oestrogen in the MSG-treated animals significantly altered. Besides, the average uterine lumen area (µm2) was smaller than the control group. MSG showed high-affinity binding to acetylcholine receptors and disrupted the normal nerve signal with a predicted LD50 of 4500 mg/kg. MSG also demonstrated good binding affinity to human oestrogen receptors beta and some other proteins that have an oxidative stress role in the female reproductive organs. Therefore, a precaution should be taken when utilising this compound, especially for females under the risk factor of hormonal abnormality.

Therapeutic Potential of Certain Terpenoids as Anticancer Agents: A Scoping Review.

Cancer is a life-threatening disease and is considered to be among the leading causes of death worldwide. Chemoresistance, severe toxicity, relapse and metastasis are the major obstacles in cancer therapy. Therefore, introducing new therapeutic agents for cancer remains a priority to increase the range of effective treatments. Terpenoids, a large group of secondary metabolites, are derived from plant sources and are composed of several isoprene units. The high diversity of terpenoids has drawn attention to their potential anticancer and pharmacological activities. Some terpenoids exhibit an anticancer effect by triggering various stages of cancer progression, for example, suppressing the early stage of tumorigenesis via induction of cell cycle arrest, inhibiting cancer cell differentiation and activating apoptosis. At the late stage of cancer development, certain terpenoids are able to inhibit angiogenesis and metastasis via modulation of different intracellular signaling pathways. Significant progress in the identification of the mechanism of action and signaling pathways through which terpenoids exert their anticancer effects has been highlighted. Hence, in this review, the anticancer activities of twenty-five terpenoids are discussed in detail. In addition, this review provides insights on the current clinical trials and future directions towards the development of certain terpenoids as potential anticancer agents.

Diosmetin Exerts Synergistic Effects in Combination with 5-Fluorouracil in Colorectal Cancer Cells.

5-Fluorouracil (5-FU) is a chemotherapeutic medication commonly used to treat colorectal cancer (CRC); however, the drug-associated adverse effects and toxicity have greatly affected its clinical use. Exploring another therapeutic strategy that lowers the toxicity of 5-FU while having a synergistic effect against CRC is thus a viable option. Diosmetin, a natural flavonoid, has been shown to inhibit the proliferation of many cancer cells, including CRC cells. This study aims to investigate the synergistic effect of diosmetin and 5-FU on HCT116 and HT29 colorectal cancer cells and to explore the apoptotic activity of this combination. The MTT assay was used to assess the viability of cells treated with monotherapy and combination therapy. The combination index (CI) and dose reduction index (DRI) were calculated using the CompuSyn software (version 1.0). The SynergyFinder 2.0 software was used to calculate the synergy score, while the Combenefit software was employed to perform isobologram analysis and synergism determination. The AO/PI double staining technique was used to detect the apoptotic characteristics of cells, whereas the flow cytometry technique was used to investigate the apoptosis induction and cell cycle arrest in cells. The combination of 5-FU and diosmetin showed a synergistic effect in HCT116 cells with a mean CI value of 0.66 ± 0.4, and an additive effect in HT29 cells with a CI value of 1.0 ± 0.2. The DRI of 5-FU in HCT116 cells was three times lower in the combination therapy compared to monotherapy of 5-FU. AO/PI microscopic examination and Annexin V analysis revealed that the combination-treated cells had more apoptotic cells than the monotherapy-treated cells, which was activated mainly through intrinsic apoptosis pathway. HCT116 cell death was confirmed by mitotic arrest in the G2/M phase. Our findings suggest that 5-FU/diosmetin combination exhibits synergistic effect against HCT116 cancer cells, and potentially reduces the unfavorable adverse effect of 5-FU while enhancing the anticancer efficacy by inducing apoptosis and interrupting mitosis. Further research studies are needed to validate the combination's anti-tumorigenic activities in a xenograft animal model.

Asperginols A and B, Diterpene Pyrones, from an Aspergillus sp. and the Structure Revision of Previously Reported Analogues.

Two new diterpene pyrones, asperginols A (1) and B (2), and four known analogues (3-6) were isolated from the endophytic fungus Aspergillus sp. HAB10R12. The structures and absolute configurations of these compounds were elucidated based on the analysis of their NMR, MS, and X-ray diffraction data. The revision of the absolute configurations at C-10, C-11, and C-14 of the known diterpene pyrones (3-6) and the determination of the configuration at the polyene side chain for compounds (4-6) were made using chemical methods and vibrational circular dichroism analysis. This group of diterpene pyrone compounds showed unique structural features including a 7/6/6 tricyclic diterpene moiety with an unusual trans-syn-trans stereochemical arrangement. Compound 6 showed moderate activity against the HT-29 colon cancer cell line.