Molecular Mechanisms and Modulation of Key Pathways Underlying the Synergistic Interaction of Sorafenib with Erlotinib in Non-Small-Cell-Lung Cancer (NSCLC) Cells

Giovannetti, E.; Labots, M.; Dekker, H.; Galvani, E.; Lind, J.S.W.; Sciarrillo, R.; Honeywell, R.; Smit, E.F.; Verheul, H.M.; Peters, G.J.

doi:10.2174/13816128130511

Cited by 8 publications

(8 citation statements)

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“…Previous studies have shown that sorafenib alone inhibited the growth of NSCLC cells, and its combination with other drugs, such as gemcitabine or erlotinib, could increase the inhibitory effect in NSCLC cells or mouse models. (34,35) The effectiveness of betulinic acid and other betulin derivatives in combination with chemotherapy or other target drugs is poorly explored. Only the synergistic effect of betulin with acyclovir and rimantadine was measured against herpes simplex and influenza viruses.…”

Section: Discussionmentioning

confidence: 99%

Synergistic activity of sorafenib and betulinic acid against clonogenic activity of non‐small cell lung cancer cells

2017

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The highly selective multi‐targeted agent sorafenib is an inhibitor of a number of intracellular signaling kinases with anti‐proliferative, anti‐angiogenic and pro‐apoptotic effects in various types of tumors, including human non‐small cell lung cancer (NSCLC). Betulin displays a broad spectrum of biological and pharmacological properties, including anticancer and chemopreventive activity. Combination of drugs with different targets is a logical approach to overcome multilevel cross‐stimulation among key signaling pathways in NSCLC progression. NSCLC cell lines, A549, H358 and A427, with different KRAS mutations, and normal human peripheral blood lymphocyte cells, were treated with sorafenib and betulinic acid alone and in combination. We examined the effect of different combined treatments on viability (MTS test), proliferation and apoptotic susceptibility based on flow cytometry, alterations in signaling pathways by western blotting and colony‐forming ability. The combination of sorafenib with betulinic acid had a strong effect on the induction of apoptosis of different NSCLC cell lines. In addition, this combination was not toxic for human peripheral blood lymphocytes. Combination treatment changed the expression of proteins involved in the mitochondrial apoptosis pathway and induced apoptotic death by caspase activation. Importantly, combination treatment with low drug concentrations tremendously reduced the colony‐forming ability of A549, H358 and A427 cells, as compared to both compounds alone. In this study, we showed that combination therapy with low concentrations of sorafenib and betulinic acid had the capacity to induce high levels of cell death and abolish clonogenic activity in some NSCLC cell lines regardless of KRAS mutations.

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Section: Discussionmentioning

confidence: 99%

Synergistic activity of sorafenib and betulinic acid against clonogenic activity of non‐small cell lung cancer cells

2017

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“…Microtubule stabilization analysis NSCLC cells H23 (CYP1B1 4326CC) and H322 (CYP1B1 4326GG) were selected after CYP1B1 genotyping of 12 NSCLC (H23, H322, H460, H1703, H292, H3255, H1975, H1650, A549 and SW1573) and maintained as monolayer cultures in RPMI or DMEM (containing 2 mM l-glutamine) supplemented with 10 % heat-inactivated FBS, penicillin (50 IU/ml) and streptomycin (50 µg/ml), as described previously (Giovannetti et al 2013).…”

Section: Evaluation Of Snpsmentioning

confidence: 99%

Cytochrome P450 1B1 (CYP1B1) polymorphisms are associated with clinical outcome of docetaxel in non-small cell lung cancer (NSCLC) patients

Vasile

Tibaldi

León

et al. 2014

J Cancer Res Clin Oncol

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“…In conclusion, sorafenib inhibited the proliferation of A549/DDP cisplatin-resistant lung adenocarcinoma cells in a time-and concentration-dependent manner. Sorafenib also induces apoptosis and reduces the invasiveness of A549/DDP cells, which provided scientific experimental evidence for the theoretical basis of the application of sorafenib in the subsequent treatment of cisplatin-resistant lung cancer and offers a novel and effective strategy for further treatment of advanced lung cancer (13)(14)(15).…”

Section: Discussionmentioning

confidence: 94%

Therapeutic effects of sorafenib on the A549/DDP human lung adenocarcinoma cell line in vitro

Chen

Wang

et al. 2014

Molecular Medicine Reports

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The aim of the present study was to observe the effects of sorafenib on the proliferation, apoptosis and invasion of A549/DDP cisplatin-resistant lung adenocarcinoma cells cultured in vitro. The A549/DDP cisplatin-resistant lung adenocarcinoma cell strain was cultured in vitro, the cell culture group incubated in culture medium only was set as the control group (Group S0) and the four concentration gradients of sorafenib were added to the culture groups as the experimental groups: S1, 2 µmol/l; S2, 4 µmol/l; S3, 8 µmol/l; and S4, 16 µmol/l. The MTT assay was used to determine the growth inhibition rate of the cells, which were respectively subjected to sorafenib treatment for 24, 48 and 72 h. Flow cytometry was used to determine the rate of apoptosis of cells in each group following sorafenib treatment for 72 h. Furthermore, the Transwell invasion experiment was used to determine the effect on A549/DDP cell invasion following sorafenib treatment for 24 h. Based on the MTT assay, it was found that the inhibition rates of A549/DDP cisplatin-resistant lung adenocarcinoma cells in groups S1-4 following sorafenib treatment for 24 h were 4.58±2.82, 14.93±2.62, 37.58±7.13 and 58.39±8.15%, respectively. For 48 h, inhibition rates in S1-4 were 14.98±2.93, 26.28±7.31, 63.00±3.05 and 78.84±3.96%, respectively, and for 72 h, inhibition rates were 18.80±2.82, 32.71±2.55, 75.51±4.73 and 87.50±3.36%, respectively. The difference in the inhibition rates of cells among the experimental groups for the same incubation time showed statistical significance (P<0.05). Flow cytometric analysis indicated that the rate of apoptosis in the control group was 8.88±0.81% following sorafenib treatment for 72 h, and the rates of apoptosis in groups S1-4 were, 12.84±0.24, 17.27±0.78, 21.98±0.75 and 49.67±1.38%, respectively. The rate of apoptosis in each experimental group was higher compared with that in the control group (P<0.05). The difference in the rate of apoptosis among the experimental groups was statistically significant (P<0.05). The Transwell assay showed that the number of cells permeating the septum in the control group was 82.7±2.3/high power lens (HP), while the average number of cells permeating septum in groups S1-4 following treatment with sorafenib for 24 h was 58.2±2.5, 41.3±1.3, 22.6±2.1 and 14.7±1.1/HP, which was significantly lower compared with the control group. The number of cells permeating the septum in each experimental group decreased with the enhancement of the concentration gradient. The differences were statistically significant (P<0.05). In conclusion, sorafenib inhibits the proliferation of A549/DDP cisplatin‑resistant lung adenocarcinoma cells in a time‑ and concentration‑dependent manner. In addition, sorafenib induces apoptosis in A549/DDP cisplatin‑resistant lung adenocarcinoma cells, thus reducing their invasiveness.

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Molecular Mechanisms and Modulation of Key Pathways Underlying the Synergistic Interaction of Sorafenib with Erlotinib in Non-Small-Cell-Lung Cancer (NSCLC) Cells

Cited by 8 publications

References 0 publications

Synergistic activity of sorafenib and betulinic acid against clonogenic activity of non‐small cell lung cancer cells

Synergistic activity of sorafenib and betulinic acid against clonogenic activity of non‐small cell lung cancer cells

Cytochrome P450 1B1 (CYP1B1) polymorphisms are associated with clinical outcome of docetaxel in non-small cell lung cancer (NSCLC) patients

Therapeutic effects of sorafenib on the A549/DDP human lung adenocarcinoma cell line in vitro

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