Metformin synergistic pemetrexed suppresses non‐small‐cell lung cancer cell proliferation and invasion in vitro

Abstract

The aim of this study was to investigate whether metformin in combination with pemetrexed has an effect on the treatment of non‐small‐cell lung cancer (NSCLC) models and to explore the related molecular mechanism. The half maximal inhibitory concentration (IC50) and combination index (CI) of metformin and pemetrexed were detected by the CCK8 assay to assess the antiproliferative and therapeutic effects of the two‐drug combination. Flow cytometry (FCM) and invasion assays were used to estimate the variation in apoptosis rate and invasion ability of the differently treated NSCLC cell lines. Apoptotic markers were detected by western blotting to validate the data related to the antiproliferation and proapoptosis effects. Metformin monotherapy inhibited the growth of NSCLC cell lines and reduced the invasion ability to different degrees compared with the control groups (P < 0.05). Metformin in combination with pemetrexed produced a synergistic effect (CI < 0.90) compared with the two drugs in monotherapy in the three tested NSCLC cell lines. Metformin in combination with pemetrexed significantly increased the cell numbers of HCC827 cells at S phase (P < 0.001), and the combination therapy had no influence on the A549 and H1975 cell lines. We found that combining metformin with pemetrexed induced more cell apoptosis than metformin or pemetrexed used alone (P < 0.05), which was validated by the apoptotic markers. These results demonstrate that the combination of metformin and pemetrexed has a synergistic effect on the treatment of NSCLC cell lines by inducing apoptosis or blocking the cell cycle. Our data indicate that the combination of metformin and pemetrexed could have beneficial antitumor effects on NSCLC cells in vitro.

Metabolic Profiles Associated With Metformin Efficacy in Cancer

“…In murine models, combinatorial metformin treatment with the chemotherapeutic agent doxorubicin led to reduced mammary tumor mass and relapse compared to either drug alone when performing xenograft experiments ( 83 , 84 ). There is also data showing that metformin has synergistic effects with various chemotherapy agents, including Pemetrexed in cell lines of non-small cell lung cancer (NSCLC), ( 85 ) EGFR-TKI in patients with NSCLC ( 86 ), Trichostatin in osteosarcoma cell lines ( 87 ), Simvastatin in animal models of metastatic prostate cancer ( 88 ) and Nelfinavir in cervical cancer xenografts ( 89 ). It has also been suggested that metformin may lead to a re-sensitization of cancer cells that have become resistance to chemotherapy, the predominant cause of treatment failure in patients undergoing treatment ( 45 , 84 , 90 , 91 ).…”

Metformin alters therapeutic effects in the BALB/c tumor therapy model

“…Even though several anticarcinogenic effects of metformin are observed, the clinical data are still contentious depending on disease-related (type of tumor, clinical stage, form of treatment) and on patient-related factors (insulin resistance, age, sex) [ 21 ]. For in vitro experiments, the combination of metformin with several chemotherapeutic agents shows controversial results ranging from synergistic effects [ 22 – 24 ] to even adverse effects [ 25 , 26 ]. So far, these investigations underline the need for a more detailed understanding of the molecular mechanisms that occur when combining metformin with chemotherapeutics before applying it as a potential adjuvant in chemotherapy.…”

Organic anion transporters and PI3K–AKT–mTOR pathway mediate the synergistic anticancer effect of pemetrexed and rhein

“…The Bcl-2 protein family has been extensively studied among numerous apoptosis regulating factors (Ola, Nawaz, & Ahsan, 2011). Furthermore, Zhang, Feng, Li, Yi, and Li (2017) demonstrated that the combination of PTX and metformin could enhance the antitumor activity of PTX by regulating Bax and Bcl-2.…”