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The Synergistic Effect of Piperlongumine and Sanguinarine on the Non-Small Lung Cancer.

ABSTRACT: BACKGROUND:Cancers are one of the leading causes of deaths nowadays. The development of new treatment schemes for oncological diseases is an interesting direction in experimental medicine. Therefore, the evaluation of the influence of two alkaloids-piperlongumine (PL), sanguinarine (SAN) and their combination-on the basic life processes of the A549 cell line was considered reasonable. METHODS:The aim was achieved by analyzing the cytotoxic effects of PL and SAN and their combination in the ratio of 4:1 on the induction of cell death, changes in the distribution of cell cycle phases, reorganization of cytoskeleton and metastatic potential of A549 cells. The versatility of the applied concentration ratio was evaluated in terms of other cancer cell lines: MCF-7, H1299 and HepG2. RESULTS:The results obtained from the MTT assay indicated that the interaction between the alkaloids depends on the concentration and type of cells. Additionally, the compounds and their combination did not exhibit a cytotoxic effect against normal cells. The combined effects of PL and SAN increased apoptosis and favored metastasis inhibition. CONCLUSION:Selected alkaloids exhibit a cytotoxic effect on A549 cells. In turn, treatment with the combination of PL and SAN in a 4:1 ratio indicates a synergistic effect and is associated with an increase in the level of reactive oxygen species (ROS).

SUBMITTER: Halas-Wisniewska M

PROVIDER: S-EPMC7411589 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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The Synergistic Effect of Piperlongumine and Sanguinarine on the Non-Small Lung Cancer.

Hałas-Wiśniewska Marta M Zielińska Wioletta W Izdebska Magdalena M Grzanka Alina A

Molecules (Basel, Switzerland) 20200703 13

<h4>Background</h4>Cancers are one of the leading causes of deaths nowadays. The development of new treatment schemes for oncological diseases is an interesting direction in experimental medicine. Therefore, the evaluation of the influence of two alkaloids-piperlongumine (PL), sanguinarine (SAN) and their combination-on the basic life processes of the A549 cell line was considered reasonable.<h4>Methods</h4>The aim was achieved by analyzing the cytotoxic effects of PL and SAN and their combinati ...[more]

PMID: 32635287

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Project description:Epidermal growth factor receptor (EGFR) and c-MET receptors are expressed on many non-small cell lung cancer (NSCLC) cells. Current single agent therapeutic targeting of a mutant EGFR has a high efficacy in the clinic, but is not curative. Here, we investigated the combination of targeting EGFR and c-MET pathways in NSCLC cells resistant to receptor tyrosine kinase inhibitors (TKIs), using RNA interference and inhibition by TKIs. Different NSCLC cell lines with various genomic characteristics (H358, H1650 and H1975) were transfected with EGFR-specific-siRNA, T790M-specific-siRNA, c-MET siRNA or the combination. Subsequently EGFR TKIs (gefitinib, erlotinib or afatinib) or monoclonal antibody cetuximab were combined respectively with the c-MET-specific TKI su11274 in NSCLC cell lines. The cell proliferation, viability, caspase-3/7 activity and apoptotic morphology were monitored by spectrophotometry, fluorimetry and fluorescence microscopy. The combined effect of EGFR TKIs, or cetuximab and su11274, was evaluated using a combination index. The results showed that the cell lines that were relatively resistant to EGFR TKIs, especially the H1975 cell line containing the resistance T790M mutation, were found to be more sensitive to EGFR-specific-siRNA. The combination of EGFR siRNA plus c-MET siRNA enhanced cell growth inhibition, apoptosis induction and inhibition of downstream signaling in EGFR TKI resistant H358, H1650 and H1975 cells, despite the absence of activity of the c-MET siRNA alone. EGFR TKIs or cetuximab plus su11274 were also consistently superior to either agent alone. The strongest biological effect was observed when afatinib, an irreversible pan-HER blocker was combined with su11274, which achieved a synergistic effect in the T790M mutant H1975 cells. In a conclusion, our findings offer preclinical proof of principle for combined inhibition as a promising treatment strategy for NSCLC, especially for patients in whom current EGFR-targeted treatments fail due to the presence of the T790M-EGFR-mutation or high c-MET expression.

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The Synergistic Effect of Piperlongumine and Sanguinarine on the Non-Small Lung Cancer.

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The Synergistic Effect of Piperlongumine and Sanguinarine on the Non-Small Lung Cancer.

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