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Synergistic Antitumor Activity of SH003 and Docetaxel via EGFR Signaling Inhibition in Non-Small Cell Lung Cancer.

ABSTRACT: Epidermal growth factor receptor (EGFR) is overexpressed in lung cancer patients. Despite treatment with various EGFR tyrosine kinase inhibitors, recurrence and metastasis of lung cancer are inevitable. Docetaxel (DTX) is an effective conventional drug that is used to treat various cancers. Several researchers have studied the use of traditional herbal medicine in combination with docetaxel, to improve lung cancer treatment. SH003, a novel herbal mixture, exerts anticancer effects in different cancer cell types. Here, we aimed to investigate the apoptotic and anticancer effects of SH003 in combination with DTX, in human non-small-cell lung cancer (NSCLC). SH003, with DTX, induced apoptotic cell death, with increased expression of cleaved caspases and cleaved poly (ADP-ribose) polymerase in NSCLC cells. Moreover, SH003 and DTX induced the apoptosis of H460 cells via the suppression of the EGFR and signal transducer and activator of transcription 3 (STAT3) signaling pathways. In H460 tumor xenograft models, the administration of SH003 or docetaxel alone diminished tumor growth, and their combination effectively killed cancer cells, with increased expression of apoptotic markers and decreased expression of p-EGFR and p-STAT3. Collectively, the combination of SH003 and DTX may be a novel anticancer strategy to overcome the challenges that are associated with conventional lung cancer therapy.

SUBMITTER: Jeong MS

PROVIDER: S-EPMC8395077 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Synergistic Antitumor Activity of SH003 and Docetaxel via EGFR Signaling Inhibition in Non-Small Cell Lung Cancer.

Jeong Mi-So MS Lee Kang-Wook KW Choi Yu-Jeong YJ Kim Yun-Gyeong YG Hwang Hyun-Ha HH Lee Seo-Yeon SY Jung Se-Eun SE Park Sun-Ah SA Lee Jin-Hee JH Joo Yong-Joon YJ Cho Sung-Gook SG Ko Seong-Gyu SG

International journal of molecular sciences 20210805 16

Epidermal growth factor receptor (EGFR) is overexpressed in lung cancer patients. Despite treatment with various EGFR tyrosine kinase inhibitors, recurrence and metastasis of lung cancer are inevitable. Docetaxel (DTX) is an effective conventional drug that is used to treat various cancers. Several researchers have studied the use of traditional herbal medicine in combination with docetaxel, to improve lung cancer treatment. SH003, a novel herbal mixture, exerts anticancer effects in different c ...[more]

PMID: 34445110

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Project description:BackgroundDespite the introduction of several novel therapeutic approaches that improved survival, metastatic castration-resistant prostate cancer (mCRPC) remains an incurable disease. Herein we report the synergistic antitumor interaction between two well-known drugs used for years in clinical practice, the antiepileptic agent with histone deacetylase inhibitory activity valproic acid and the cholesterol lowering agent simvastatin, in mCRPC models.MethodsSynergistic anti-tumor effect was assessed on PC3, 22Rv1, DU145, DU145R80, LNCaP prostate cancer cell lines and EPN normal prostate epithelial cells, by calculating combination index (CI), caspase 3/7 activation and colony formation assays as well as on tumor spheroids and microtissues scored with luminescence 3D-cell viability assay. Cancer stem cells (CSC) compartment was studied evaluating specific markers by RT-PCR, western blotting and flow cytometry as well as by limiting dilution assay. Cholesterol content was evaluated by 1H-NMR. Overexpression of wild-type YAP and constitutively active YAP5SA were obtained by lipofectamine-based transfection and evaluated by immunofluorescence, western blotting and RT-PCR. 22Rv1 R_39 docetaxel resistant cells were selected by stepwise exposure to increasing drug concentrations. In vivo experiments were performed on xenograft models of DU145R80, 22Rv1 parental and docetaxel resistant cells, in athymic mice.ResultsWe demonstrated the capacity of the combined approach to target CSC compartment by a novel molecular mechanism based on the inhibition of YAP oncogene via concurrent modulation of mevalonate pathway and AMPK. Because both CSCs and YAP activation have been associated with chemo-resistance, we tested if the combined approach can potentiate docetaxel, a standard of care in mCRCP treatment. Indeed, we demonstrated, both in vitro and in vivo models, the ability of valproic acid/simvastatin combination to sensitize mCRPC cells to docetaxel and to revert docetaxel-resistance, by mevalonate pathway/YAP axis modulation.ConclusionOverall, mCRPC progression and therapeutic resistance driven by CSCs via YAP, can be tackled by the combined repurposing of two generic and safe drugs, an approach that warrants further clinical development in this disease.

Project description:BackgroundClinical features of epidermal growth factor receptor (EGFR) mutations have been commonly recognized in variant cancers. The role of EGFR mutations in non-small cell lung cancer (NSCLC) has spurred research and drug development efforts. However, there are still mutations that have not been widely reported, and their influences on NSCLC have not been fully elucidated; EGFR G873R mutation is just one of them. The aim of this study was to investigate the correlation between EGFR G873R mutation and the prognosis of chemotherapy in NSCLC.MethodsA total of 54 patients with NSCLC were enrolled in this study. Immunohistochemical staining was used to detect the expression of EGFR. A DNA extraction kit (GeneRead DNA FFPE Kit) was used to extract total DNA from resected cancer tissues. Genomic DNA targets were amplified by polymerase chain reaction (PCR), and then the amplicons were purified and sequenced. Statistical methods were performed to detect the relationship between EGFR G873R mutation and various clinicopathological features and the effect of EGFR G873R mutation on the prognosis of chemotherapy.ResultsEGFR G873R mutation did not show statistical significance, with EGFR high expression identified in 30 cases (P>0.05). Patients with EGFR G873R mutation had a significantly favorable prognosis of docetaxel (P=0.032), and for patients treated with docetaxel, EGFR G873R mutation was significantly correlated with better 5-year disease-free survival (DFS; P=0.026) and overall survival (OS; P=0.026). However, there was no statistical significance found between EGFR G873R mutation and the prognosis of vinorelbine (P>0.05), and for patients treated with vinorelbine, EGFR G873R mutation had no statistical significance with 5-year DFS (P>0.05) and OS (P>0.05).ConclusionsEGFR G873R mutation was remarkably correlated with the prognosis of docetaxel in NSCLC, which indicates that EGFR G873R may be employed as a promising biomarker to identify individuals with better prognosis of docetaxel and as an antitumor target for NSCLC treatment.

Dataset Information

Synergistic Antitumor Activity of SH003 and Docetaxel via EGFR Signaling Inhibition in Non-Small Cell Lung Cancer.

Publications

Synergistic Antitumor Activity of SH003 and Docetaxel via EGFR Signaling Inhibition in Non-Small Cell Lung Cancer.

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