Gemcitabine and Selected mTOR Inhibitors in Uterine Sarcomas and Carcinosarcoma Cells- an Isobolographic Analysis

Bobinski, M.; Okła, Karolina; Łuszczki, Jarogniew J.; Bednarek, Wiesława; Wawruszak, Anna; Moreno‐Bueno, Gema; García-Sanz, Pablo; Dmoszyńska‐Graniczka, Magdalena; Tarkowski, Rafał; Kotarski, Jan

doi:10.7150/ijms.48187

Cited by 9 publications

(6 citation statements)

References 28 publications

(50 reference statements)

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“…Isobolographic analysis is a statistical method that has been widely used to assess drug interactions. This method is based on the cytotoxicity experiments completed on treated cells with both drugs and the mixture [12]. The ATO and GCB combination showed synergistic anti-cancer activity (CI < 1) in both cancer cell lines (CI: 0.83 for MCF-7 and 0.88 for MDA-MB-231).…”

Section: Resultsmentioning

confidence: 99%

Arsenic Trioxide Synergistically Enhances the Anti-Neoplastic Effect of Gemcitabine on Breast Cancer Cells by Promoting Mitochondrial Dysfunction

Maleki

Handali

Rezaei

2023

Preprint

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Breast cancer is the most common type of cancer in women worldwide. A common approach to cancer treatment in clinical practice is to use a combination of drugs to enhance the anticancer activity of drugs while reducing their side effects. In this regard, we evaluated the effectiveness of combined treatment with gemcitabine (GCB) and arsenic (ATO) and how they affect the cell death pathway in cancer cells. Cytotoxic activity of drugs individually or combined against MDA-MB-231 and MCF-7 was performed by MTT method and isobolographic analysis was used to determine the interaction between these factors. The combination of ATO and GCB showed synergistic anti-cancer activity (CI < 1) in both cancer cell lines. The combination of ATO and GCB induced sub-G1 phase arrest, apoptosis and death rates in MCF-7 and MDA-MB-231 cells. The apoptotic response induced by the combination of GCB and ATO was dependent on caspase 3/7. Combined treatment with MMP reduction and increased ROS production caused mitochondrial dysfunction. Co-treatment significantly reduced CAT activity in both cancer cells compared to the control group and cells treated with each monotherapy. A significant decrease in cellular GSH was observed in cancer cells treated with ATO and GCB. In addition, migration and invasion were significantly reduced in breast cancer cells treated with the combination of ATO and GCB compared to cells treated with ATO and GCB. In conclusion, the combined treatment of ATO and GCB synergistically increased the anti-cancer activity, and these findings provide an effective approach for the treatment of breast cancer. To the best of our knowledge, this is the first study showing promising results for combination therapy with ATO and GCB in breast cancer.

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Section: Resultsmentioning

confidence: 99%

Arsenic Trioxide Synergistically Enhances the Anti-Neoplastic Effect of Gemcitabine on Breast Cancer Cells by Promoting Mitochondrial Dysfunction

Maleki

Handali

Rezaei

2023

Preprint

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“…Gemcitabine has been reported to inhibit cell growth, induce apoptosis, and activate autophagy via the AMP-activated protein kinase (AMPK) pathway (Zhu et al, 2018). It has also been reported as a crucial factor for gemcitabine resistance in many types of cancer (Kagawa et al, 2012;Chawsheen and Dash, 2021) and gemcitabine combined with mTOR inhibitor can sensitize the leiomyosarcoma cell line (Bobinski et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Atractylodin and β-eudesmol from Atractylodes lancea (Thunb.) DC. Inhibit Cholangiocarcinoma Cell Proliferation by Downregulating the Notch Signaling Pathway

Vanaroj

Chai่jaroenkul

Na‐Bangchang

2023

Asian Pac J Cancer Prev

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Objective: Notch signaling pathway has been reported to be involved in the development and progression of various types of cancer, including cholangiocarcinoma (CCA). Compounds that modulate this signaling pathway could be promising candidates for CCA treatment and control. The study investigated the antiproliferative activities and modulatory effects of atractylodin and β-eudesmol, the two bioactive compounds of Atractylodes lancea (Thunb.) DC. , on Notch signaling and upstream molecules (Notch1 and Notch2 receptors, JAG1, mTOR, PI3K, and YAP), and downstream molecules (Snail) in HuCCT-1 (CCA cell line) and OUMS-36T-1 (normal fibroblast cell line). Gemcitabine (standard drug for CCA), and Notch inhibitors (DAPT and zebularine) were included in the experiments as positive control compounds. Methods: The antiproliferative activity was evaluated using MTT assay. mRNA and protein expression of Notch signaling molecules were evaluated using real-time PCR and Western blot analysis. Results: Atractylodin and β-eudesmol moderately inhibited HuCCT-1 cell growth with IC 50 (concentration that inhibits cell growth by 50%) of 29.00 ± 6.44 and 16.80 ± 4.41 µg/ml (mean±SD), respectively. The direction and extent of the modulatory effects on mRNA and protein expression in the CCA cell line varied with the signaling molecules. Notch1 receptor was shown to be the most promising target of atractylodin and β-eudesmol in CCA. The level of gene expression was significantly downregulated (0.042 to 0.195 fold of control) after treating HuCC-T1 cells with both compounds at low and high concentrations. The extent and change in Notch1 gene expression correlated well with protein expression. Conclusion:The notch signaling pathway could be a promising target of atractylodin and β-eudesmol in CCA.

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“…Several pre-clinical models have shown a synergistic effect of combining mTOR inhibitors with gemcitabine (15)(16)(17)(18)(19)(20)(21)(22). Mechanistically, gemcitabine has shown to induce hyperactivation of the AKT/PI3K/ mTOR pathway which is targeted and reversed by mTOR inhibitors (14,18,20).…”

Section: Discussionmentioning

confidence: 99%

Case report: Responses to the combination of gemcitabine with sirolimus in two patients with TSC-mutated sarcomas

Nassif

Joseph²,

Lazcano³

et al. 2023

Front. Oncol.

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TSC-mutated sarcomas are rare molecular and histologic types of sarcoma. Due to the presence of their specific oncogenic driver mutation, these sarcomas are particularly sensitive to mTOR inhibitors. Recently, nab-sirolimus, an albumin-bound mTOR inhibitor, was approved by the Food and Drug Administration (FDA) for PEComas, which harbor a TSC mutation, and this drug remains the only FDA-approved systemic treatment for these tumors. We report on two cases of patients with TSC-mutated sarcomas who experienced significant responses to the combination of gemcitabine and sirolimus, after progression on prior gemcitabine-based chemotherapy and single agent mTOR inhibition with nab-sirolimus. Preclinical and clinical data support rationale for a synergistic effect of the combination. This combination may represent a valid therapeutic option after failure of nab-sirolimus in these patients, with no standard-of-care treatment options.

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Gemcitabine and Selected mTOR Inhibitors in Uterine Sarcomas and Carcinosarcoma Cells- an Isobolographic Analysis

Cited by 9 publications

References 28 publications

Arsenic Trioxide Synergistically Enhances the Anti-Neoplastic Effect of Gemcitabine on Breast Cancer Cells by Promoting Mitochondrial Dysfunction

Arsenic Trioxide Synergistically Enhances the Anti-Neoplastic Effect of Gemcitabine on Breast Cancer Cells by Promoting Mitochondrial Dysfunction

Atractylodin and β-eudesmol from Atractylodes lancea (Thunb.) DC. Inhibit Cholangiocarcinoma Cell Proliferation by Downregulating the Notch Signaling Pathway

Case report: Responses to the combination of gemcitabine with sirolimus in two patients with TSC-mutated sarcomas

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