The Synergistic Reducing Drug Resistance Effect of Cisplatin and Ursolic Acid on Osteosarcoma through a Multistep Mechanism Involving Ferritinophagy

Increasing evidence suggests that traditional Chinese medicine strategies are obviously beneficial for cancer treatment, but scientific research on the underlying molecular mechanisms is lacking. We report that ursolic acid, a bioactive ingredient isolated from Radix Actinidiae chinensis, has strong antitumour effects on osteosarcoma cells. Functional studies showed that ursolic acid inhibited tumour cell proliferation and promoted the apoptosis of a variety of osteosarcoma cells. Ursolic acid had a synergistic cytotoxic effect with cisplatin on osteosarcoma cells. In a mouse osteosarcoma xenograft model, low-dose cisplatin combined with ursolic acid significantly reduced tumour growth. Notably, ursolic acid reversed weight loss in mice treated with cisplatin. Mechanistic studies showed that ursolic acid degraded ferritin by activating autophagy and induced intracellular overload of ferrous ions, leading to ferroptosis. In addition, ursolic acid enhanced the DNA-damaging effect of cisplatin on osteosarcoma cells. Taken together, these findings suggest that ursolic acid is a nontoxic adjuvant that may enhance the effectiveness of chemotherapy in osteosarcoma.

Synergistic Cytotoxic Effect of Honey Bee Venom and Cisplatin on Tongue Squamous Cell Carcinoma Cell Line

BACKGROUND: Tongue cancer is one of the most common head and neck cancers in the world. Nowadays, natural compounds are important resources of many anti-cancer drugs. Venom from honey bees possesses potent anti-cancer activities. Cisplatin is a chemotherapeutic drug that has been used for decades to treat cancer cells. Recently, combination therapy has been a popular treatment choice for cancer patients. AIM: This study was conducted to evaluate the synergistic cytotoxic effect of honey bee venom (BV) and cisplatin on tongue squamous cell carcinoma 25 (SCC-25) cell lines. METHODS: The cytotoxic effect was determined using methyl thiazol tetrazolium assay, microscopic examination, real-time polymerase chain reaction (RT-PCR), and statistical analysis. RESULTS: The findings revealed that the cytotoxic potential of the tested drugs on SCC-25 cells was dose-dependent. Microscopic examination showed that BV and cisplatin alone and in combination mainly produced apoptotic cell death. Regarding RT-PCR results, P53 and caspase-3 expression levels were significantly increased in SCC-25-treated cells (p = 0.0001). CONCLUSION: The combined use of BV and cisplatin induced a marked synergistic cytotoxic effect on SCC-25 cell line.

Synergistic Cytotoxic Effect of Honey bee venom and Cisplatin on Tongue Squamous Cell Carcinoma

Background: Cancer is a serious issue that has a significant effect on the health of all human communities. Tongue cancer is one of the most common head and neck cancers in the world. In the medical world, cancer therapy is a major challenge. Nowadays, natural compounds are important resources of many anti-cancer medications. Venom from honey bees possesses potent anti-cancer effects. Cisplatin is a chemotherapeutic drug that has been used for decades to treat cancer cells. Recently, Combination therapy has been a popular treatment choice for cancer patients.This study aimed to investigate the synergistic cytotoxic effect of honey bee venom (BV) and cisplatin on tongue squamous cell carcinoma cell line (SCC-25).Methods: The cytotoxic effect was determined using Methyl Thiazol Tetrazolium (MTT) assay, microscopic examination, P53 and caspase-3 were quantified by Real-Time Polymerase chain reaction (RT-PCR) and statistical analysis.Results: The findings revealed that the tested drugs' cytotoxic potential against SCC-25 cells is dose dependent. The half-maximal inhibitory concentration (IC50) value of MTT assay of BV/cisplatin mix decreased significantly compared to IC50 values of BV and cisplatin in sole formulation. Microscopic examination showed that BV and cisplatin alone and in combination mainly produced apoptotic cell death. Regarding RT-PCR results, P53 and caspase-3 expression were significantly increased in SCC-25-treated cells (P= 0.0001).Conclusions: The combined use of BV and cisplatin induced marked synergistic cytotoxic effect on SCC-25 cell line.

Synergistic Cytotoxicity Effect of 5-fluorouracil and SHP2 Inhibitor Demethylincisterol A3 on Cervical Cancer Cell

Background: Demethylincisterol A3 (DTA3) has been identified as an SHP2 inhibitor and suppresses the growth of many cancer cells. 5-Fluorouracil (5-FU) is widely used for the clinical treatment of various cancers. However, the combined effects of 5-FU and DTA3 on cervical cancer cells remain unknown. Objective: his study evaluates the mechanism of the combined effects of 5-FU and DTA3 in cervical cancer cells. Methods: The synergistic cytotoxic effects of 5-FU and DTA3 in cervical cancer cells were calculated. Apoptosis was analysed by flow cytometry. Western blot analyses were used to examine the related signalling pathways. Results: DTA3 and 5-FU synergized to induce apoptosis and repress proliferation of cervical cancer cells by downregulating the activation of PI3K/AKT and NF-κB signalling pathway. We provided evidence that the upregulation of SHP2 expression by transfection significantly inhibited the cytotoxicity of 5-FU and DTA3. SHP2 knockdown enhanced the antiproliferation activity of 5-FU, indicating targeting SHP2 sensitized cervical cancer cells to 5-FU. Conclusion: Our study demonstrates that SHP2 inhibitor DTA3 and 5-FU have a synergistic cytotoxic effect on cervical cancer cells. The synergistic combination of SHP2 inhibitor and 5-FU may present a promising strategy for the treatment of cervical cancer.

Chemosensitizing micelles self-assembled from amphiphilic TPGS-indomethacin twin drug for significantly synergetic multidrug resistance reversal

Vitamin E d-ɑ-tocopheryl poly(ethylene glycol) 1000 succinate (TPGS) and indomethacin (IDM) can reverse multidrug resistance (MDR) via inhibiting P-glycoprotein (P-gp) and multidrug resistance associated protein 1 (MRP1) respectively, but their drawbacks in physicochemical properties limit their clinical application. To overcome these defects and enhance MDR reversal, the amphiphilic TPGS-IDM twin drug was successfully synthesized via esterification, and could self-assemble into free and paclitaxel-loaded (PTX-loaded) micelles. The micelles exhibited lower CMC values (5.2 × 10−5 mg/mL), long-term stability in PBS (pH 7.4) for 7 days and SDS solution (5 mg/mL) for 3 days, and effective drug release at esterase/pH 5.0. Moreover, the micelles could down-regulate ATP levels and promote ROS production in MCF-7/ADR via the mitochondrial impairment, therefore achieving MDR reversal and cell apoptosis. Additionally, the PTX-loaded micelles could significantly inhibit the cell proliferation and promote apoptosis for MCF-7/ADR via the synergistic chemosensitizing effect of TPGS and IDM, and synergistic cytotoxic effect of TPGS and PTX. Thus, the chemosensitizing micelles self-assembled from amphiphilic TPGS-indomethacin twin drug have the great potentials for reversing MDR in clinical cancer therapy.