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Osthole Synergizes With HER2 Inhibitor, Trastuzumab in HER2-Overexpressed N87 Gastric Cancer by Inducing Apoptosis and Inhibition of AKT-MAPK Pathway.

ABSTRACT: Background and Purpose: Although trastuzumab has shown considerable activity in the treatment of HER2-positive breast and gastric cancers, a significant proportion of patients do not respond to trastuzumab. Recent studies revealed that osthole, an active coumarin isolated from Cnidium monnieri (L.) Cusson possesses potent anti-tumor activity. Here, we for the first time investigated the anti-tumor activity of trastuzumab in combination with osthole in HER2-overexpressing cancers. Materials and Methods: N87 and SK-BR-3 cell lines, which were HER2-overexpressing cancer cells were used in our study. Cell Counting Kit-8 (CCK-8) assay was utilized to test the inhibitory effects of trastuzumab plus osthole. Combination index (CI) values were calculated using the Chou-Talalay method. Fluorescence-Activated Cell Sorter (FACS) assay was used to examine the cell cycle change and apoptosis upon combinatorial treatment. N87 tumor xenografts were established to evaluate in vivo effects of trastuzumab plus osthole. In addition, molecular mechanisms were analyzed by Western blot in vitro and in vivo. Results: As shown in our study, osthole alone exhibited effective anti-tumor activity against HER2-overexpressed N87 gastric cancer cells and SK-BR-3 breast cancer cells, which may be attributed to cell cycle arrest on G2/M phase and apoptosis. More importantly, our data demonstrated that trastuzumab plus osthole was much more potent than either agent alone in inhibiting the growth of N87 cancer cells in vitro and in vivo, which may be partly explained by the enhanced apoptosis upon the combinatorial treatment. Besides these, we also observed a significant decrease on the phosphorylation of AKT and MAPK in N87 cells when treated with trastuzumab plus osthole compared to either agent alone. Further data from N87 tumor xenografts revealed that trastuzumab plus osthole exerted their synergistic effects mainly on AKT signaling pathway. Conclusion: Collectively, these results support the clinical development of combination osthole with trastuzumab for the treatment of HER2-overexpressed gastric cancer.

SUBMITTER: Yang Y

PROVIDER: S-EPMC6277458 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Osthole Synergizes With HER2 Inhibitor, Trastuzumab in HER2-Overexpressed N87 Gastric Cancer by Inducing Apoptosis and Inhibition of AKT-MAPK Pathway.

Yang Yun Y Ren Feng F Tian Ziyin Z Song Wei W Cheng Binfeng B Feng Zhiwei Z

Frontiers in pharmacology 20181127

<b>Background and Purpose:</b> Although trastuzumab has shown considerable activity in the treatment of HER2-positive breast and gastric cancers, a significant proportion of patients do not respond to trastuzumab. Recent studies revealed that osthole, an active coumarin isolated from <i>Cnidium monnieri</i> (L.) Cusson possesses potent anti-tumor activity. Here, we for the first time investigated the anti-tumor activity of trastuzumab in combination with osthole in HER2-overexpressing cancers. < ...[more]

PMID: 30538636

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Project description:BACKGROUND:HER2-positive gastric cancer (GC) affects 7%-34% of patients with GC. Trastuzumab-based first-line treatment has become the standard of care for HER2-positive advanced gastric cancer (AGC). However, there are no clinically validated biomarkers for resistance to HER2-targeted therapies. Upregulation of PI3K pathway and tyrosine kinase receptor (TKR) alterations have been noted as molecular mechanisms of resistance in breast cancer. Our study aimed to perform a molecular characterization of HER2-positive AGC and investigate the role of PI3K/Akt/mTOR signaling pathway activation and TKR gene copy number (GCN) gains as predictive biomarkers in HER2-positive AGC treated with trastuzumab. PATIENTS AND METHODS:Forty-two HER2-positive GC samples from patients treated with trastuzumab-based first-line chemotherapy were selected. DNA samples were sequenced. PTEN and MET immunohistochemistry were also performed. RESULTS:Concurrent genetic alterations were detected in 97.1% of HER2-positive AGC. We found activation of PI3K/Akt/mTOR pathway in 52.4% of patients and TKR GCN gains in 38.1%. TKR GCN gains did not correlate with overall survival (OS) or progression-free survival (PFS). Multivariate Cox models showed that PI3K/Akt/mTOR activation negatively affects the effectiveness of trastuzumab-based chemotherapy in terms of OS and PFS. CONCLUSION:Our results provide for the first time a detailed molecular profile of concurrent genetic alterations in HER2-positive AGC. PI3K pathway activation could be used as a predictive marker of worse outcome in this patient population. In addition, gains in copy number of other TKR genes in this subgroup may also influence the survival benefit obtained with trastuzumab. IMPLICATIONS FOR PRACTICE:This article reports, for the first time, a detailed molecular profile of genomic alterations in patients with HER2-positive advanced gastric cancer (AGC). PI3K/Akt/mTOR signaling pathway activation seems to have a differentially negative effect on overall survival and progression-free survival in AGC treated with trastuzumab-based chemotherapy. Combining different targeted agents could be a successful therapeutic strategy to improve the prognosis of HER2-positive AGC.

Project description:For optimum radioimmunotherapy (RIT), deep penetration and uniform distribution into the tumor core is important. The solid tumor microenvironment, consisting of a highly fibrotic or desmoplastic tumor, abnormal tumor vasculature, high fluid pressure, and the absence of fluid lymphatics, limits the distribution of monoclonal antibodies mAbs to the tumor core. To investigate the optimal rationale for therapeutic mAbs administration and the microdistribution of mAbs, single and serial fractional dosage regimens of Cu-64-trastuzumab (TRZ) with paclitaxel were evaluated. Groups of nude mice were inoculated with gastric cancer cell line NCI-N87 tumor cells. When the tumor size reached 200 ± 20 mm3, the mice were divided into two groups for injection of Alexa-647-TRZ. One group (n = 5) was injected with 15 mg/kg in a single dose (SD), and the other group (n = 5) with two doses of 7.5 mg/kg (fractionated dose (FD)). In both cases, the injections were done intravenously in combination with intraperitoneal paclitaxel either as a SD of 70 mg/kg or fractionated into two doses of 40 and 30 mg/kg. Tumors were harvested, flash frozen, and sectioned (8 µm) five days after Alexa-647-TRZ injection. Rhodamine lectin (rhodamine-labeled Ricinus communis agglutinin I, 1 mg in 0.2 mL of phosphate-buffered saline (PBS)) was intravenously injected to delineate the functional vessel for a wait time of 5 min before animal euthanization. Microscopic images were acquired with an IN Cell Analyzer. The amount of TRZ that penetrated the tumor surface and the tumor vessel was calculated by area under the curve (AUC) analysis. For RIT efficacy (n = 21), Cu-64-TRZ was injected following the same dose schedule to observe tumor volume and survival ratio for 30 days. The SD and FD regimens of Alexa-647-TRZ were observed to have no significant difference in penetration of mAbs from the tumor edge and vessel, nor was the total accumulation across the whole tumor tissue significantly different. Additionally, the SD and FD regimens of Cu-64-TRZ were not proven to be significantly efficacious. Our study reveals that SD and FD in a treatment design with Cu-64-TRZ and paclitaxel shows no significant difference in therapeutic efficacy on tumor growth inhibition in vivo in mice bearing human gastric cancer xenografts overexpressing HER2 antigen.

Dataset Information

Osthole Synergizes With HER2 Inhibitor, Trastuzumab in HER2-Overexpressed N87 Gastric Cancer by Inducing Apoptosis and Inhibition of AKT-MAPK Pathway.

Publications

Osthole Synergizes With HER2 Inhibitor, Trastuzumab in HER2-Overexpressed N87 Gastric Cancer by Inducing Apoptosis and Inhibition of AKT-MAPK Pathway.

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