salvianolic-acid-a and Lung-Neoplasms

KRAS mutation is a common driver of NSCLC, and there is a high proportion of lung cancer patients with KRAS G12C and G12D mutation. KRAS was previously considered an "undruggable" target, but the first KRAS G12C mutation-targeted drug AMG510, entered the market in 2021. However, treatments for G12D mutant tumors remain to be discovered. Salvianolic acid F (SalF), a monomer derived from the traditional Chinese medicine Salvia miltiorrhiza (SM), and KRAS had high binding affinity, especially for KRAS G12D. There is an urgent need to investigate effective and safe novel targeted therapies against KRAS G12D-driven NSCLC.. To evaluate the anticancer effect of SalF, we used KRAS-overexpressing lung cancer cells in vitro, a subcutaneous transplant tumor model, and KRAS G12D mice model in vivo. Then, the binding effect of SalF and KRAS was investigated using molecular docking, proteolytic assays and protein thermal shift assays. More critically, the PI3K/AKT signaling pathway in the lung was investigated utilizing RT-qPCR and Western Blotting.. SalF activated apoptosis signaling pathways, suppressed anti-apoptotic genes, and inhibited lung cancer cell growth. These datas suggested that SalF could effectively inhibit the growth of lung tumors with KRAS G12D mutation. SalF may be a novel inhibitor against KRAS G12D, providing a strong theoretical basis for the clinical treatment of lung cancer with KRAS mutations.

Topics: Animals; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; Humans; Lung; Lung Neoplasms; Mice; Molecular Docking Simulation; Mutation; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins p21(ras); Signal Transduction

Drug resistance is one of the leading causes of chemotherapy failure in non-small cell lung cancer (NSCLC) treatment. The purpose of this study was to investigate the role of c-met in human lung cancer cisplatin resistance cell line (A549/DDP) and the reversal mechanism of salvianolic acid A (SAA), a phenolic active compound extracted from Salvia miltiorrhiza. In this study, we found that A549/DDP cells exert up-regulation of c-met by activating the Akt/mTOR signaling pathway. We also show that SAA could increase the chemotherapeutic efficacy of cisplatin, suggesting a synergistic effect of SAA and cisplatin. Moreover, we revealed that SAA enhanced sensitivity to cisplatin in A549/DDP cells mainly through suppression of the c-met/AKT/mTOR signaling pathway. Knockdown of c-met revealed similar effects as that of SAA in A549/DDP cells. In addition, SAA effectively prevented multidrug resistance associated protein1 (MDR1) up-regulation in A549/DDP cells. Taken together, our results indicated that SAA suppressed c-met expression and enhanced the sensitivity of lung adenocarcinoma A549 cells to cisplatin through AKT/mTOR signaling pathway.

Topics: Adenocarcinoma; Alkenes; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B; Cell Line, Tumor; Cisplatin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Synergism; Humans; Lung Neoplasms; Phytotherapy; Polyphenols; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-met; Salvia miltiorrhiza; Signal Transduction; TOR Serine-Threonine Kinases; Up-Regulation

This paper was aimed to investigate the microRNA associated with multidrug resistance gene MDR1 of salvianolic acid A reversal in lung cance. Human lung cancer A549 cells were divided into normal control group and drug group, and the MDR1 expression levels were determined by real-time quantitative PCR. MicroRNA expression profiling of normal control group and drug group were detected by using the latest microRNA microarray. Quantitative RT-PCR was used to validate the differentially expressed miRNA. Forecast of miRNA associated with MDR1 multi-resistant genes of up-regulated miRNA. Experimental results showed that the dosage of MDR1 expression level significantly lowered compared with control group. The miRNA expression spectrum analyses of human lung cancer A549 cells to drug group and the control group were detected by microRNA microarray, 426 differentially expressed miRNA were screened out. Then target prediction were performed for difference up-expression of miRNA and found that there were four obvious increase of miRNA associated with MDR1 multi-resistant genes. Real-time quantitative PCR for 4 microRNA verification, the results were consistent with the chip. So the author considered that salvianolic acid A down lung cancer multidrug resistance gene MDR1 is likely to be affected by the miRNA expression and regulation of target genes, to further clarify the traditional Chinese medicine to reverse multi-drug resistant mechanism provides the experimental basis.

Topics: A549 Cells; Caffeic Acids; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Genes, MDR; Humans; Lactates; Lung Neoplasms; MicroRNAs

Salvianolic acid A (1) is one of the active components from Salvia miltiorrhiza, which was found to suppress the growth of mouse tumors. S-3-1 (a 2-allyl-3,4-dihydroxybenzaldehyde, 2) is a synthetic intermediate of a salvianolic acid A derivative with strong inhibitory effects on the growth of cancer cells in vitro. The inhibitory effects of 2 on tumor growth and its molecular targets were studied. 2 significantly suppressed the growth of mouse Lewis lung carcinoma, S180 sarcoma and H22 hepatic carcinoma in a dose-dependent manner. With a simple scrape-loading dye transfer method, 20 microg/ml of 2 was found to significantly enhance gap junction intercellular communication (GJIC) in human pancreatic adenocarcinoma PaCa Cells, human lung epithelial carcinoma W1-38 cells and human lung adenocarcinoma A549 cells, but 2 had no marked effect on GJIC in human colon cancer CACO2 cells. With Northern blot analysis, 2 was found to inhibit the expression of c-myc gene in A549 cells and have no marked effect on H-ras oncogene expression, and increase the cellular P53 mRNA contents, though it did not affect the expression of RB tumor suppressor gene. 2 also suppressed the P46 (JNK/SAPK) expression in A549 cells. Western blot analysis was applied to visualize the P21ras protein. Results shows that 2 at concentrations ranging from 10 to 20 microg/ml decreases the contents of the membranous P21ras and total P21ras and increases the contents of cytosolic P21ras protein in a time-dependent manner. However, 2 had no significant effects on farnesyl protein transferase activities at the concentrations that could efficiently decrease the membranous P21ras content. This suggested that 2 might suppress tumor growth partly through enhancement of GJIC and reversion of the transformed phenotypes. The other mechanisms may be that 2 can suppress the overexpression of c-myc oncogene, inhibit the function of Ras oncoprotein, increase the expression of P53 tumor suppressor gene and interrupt P46-associated mitogen-activated pathway other than farnesylation of Ras protein.

Topics: Allyl Compounds; Animals; Benzaldehydes; Blotting, Western; Caco-2 Cells; Caffeic Acids; Catechols; Cell Division; Dose-Response Relationship, Drug; Gene Expression Regulation, Neoplastic; Genes, myb; Genes, p53; Humans; Lactates; Liver Neoplasms; Lung Neoplasms; Mice; Mitogens; Phenotype; Sarcoma; Tumor Cells, Cultured