Blocking the PI3K/AKT and MEK/ERK signaling pathways can overcome Gefitinib-resistance in non-small cell lung cancer cell lines

Li, H; Schmid-Bindert, Gerald; Wang, D; Zhao, Yan; Yang, Xiaoyu; Su, Bin; Zhou, Caicun

doi:10.2478/v10039-011-0043-x

Cited by 79 publications

(71 citation statements)

References 21 publications

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“…H1975, A549, Pc9 gefitinibsensitive (Pc9) and Pc9 gefitinib-resistant (Pc9 GR) cells were treated with different doses of gefitinib (0 μM, 0.01 μM, 0.1 μM, 1 μM, 5 μM, 10 μM, and 20 μM) and cell growth was then detected by the CCK8 method. Consistent with previous studies (Li et al 2011), the results showed that H1975 and Pc9 cell lines were sensitive to gefitinib whereas A549 and Pc9 GR were relatively resistant ( Figure 1A). We next detected the expression of miR130a and Met in the four NSCLC cell lines by qRT-PCR or western blot.…”

Section: Mir-130a Is Overexpressed In Gefitinib-sensitive Nsclc Cell supporting

confidence: 92%

MiR-130a Overcomes Gefitinib Resistance by Targeting Met in Non-Small Cell Lung Cancer Cell Lines

Zhou

Liu²,

Sun³

2014

Asian Pacific Journal of Cancer Prevention

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Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and the most common cause of lung cancer death. Currently, the epidermal growth factor receptor inhibitor gefitinib is used for its treatment; however, drug resistance is a major obstacle. Expression of Met has been associated with both primary and acquired resistance to gefitinib, but the mechanisms regulating its expression are not fully understood. Recently, miRNAs such as miR-130a have been shown to play a role in gefitinib resistance, but importance in NSCLC and relationships with Met have not been fully explored. Here we show that miR-130a is over-expressed in gefitinibsensitive NSCLC cell lines, but is low in gefitinib-resistant NSCLC cell lines. Moreover, miR-130a expression was negatively correlated with that of Met. Further analysis revealed that over-expression of miR-130a increased cell apoptosis and inhibited proliferation of NSCLC cells treated with gefitinib, whereas lowering the expression of miR-130a decreased cell apoptosis and promoted cell proliferation after treatment with gefitinib in both gefitinib-sensitive and -resistant NSCLC cell lines, suggesting that miR-130a overcomes gefitinib resistance. We also demonstrated that miR-130a binds to the 3'-UTR of Met and significantly suppresses its expression. Finally, our results showed that over-expressing Met could "rescue" the functions of miR-130a regarding cell apoptosis and proliferation after cells are treated with gefitinib. These findings indicate that the miR-130a/Met axis plays an important role in gefitinib resistance in NSCLC. Thus, the miR-130a/Met axis may be an effective therapeutic target in gefitinib-resistant lung cancer patients.

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Section: Mir-130a Is Overexpressed In Gefitinib-sensitive Nsclc Cell supporting

confidence: 92%

MiR-130a Overcomes Gefitinib Resistance by Targeting Met in Non-Small Cell Lung Cancer Cell Lines

Zhou

Liu²,

Sun³

2014

Asian Pacific Journal of Cancer Prevention

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“…EGFR-TKIs primarily inhibit the downstream signaling pathway activity of EGFR via the PI3K/Akt signaling pathway, thereby inhibiting cell proliferation and invasion, as well as inducing apoptosis (34). The suppression of the Akt signaling pathway may preserve gefitinib resistance in NSCLC cell lines (35). It has been demonstrated that miR-21 positively regulates the PI3K/Akt signaling pathway (18,36,37).…”

Section: Discussionmentioning

confidence: 99%

Exosome‑mediated gefitinib resistance in lung cancer HCC827 cells via delivery of miR‑21

Jing

Qin

et al. 2018

Oncol Lett

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Abstract. Acquired resistance to gefitinib remains a major challenge in cancer treatment. In the present study, the effect of exosomes on the transmission of gefitinib resistance from gefitinib-resistant HCC827 lung cancer cells (H827R) to their gefitinib-sensitive counterparts and the potential underlying mechanisms by which this occurs was investigated. Exosomes were obtained from the cell supernatant using ultracentrifugation and the ExoQuick-TC exosome precipitation solution. Drug resistance was assessed by flow cytometry, apoptosis assays and cell counting kit-8 assays. The expression of microRNA (miR)-21 was analyzed by reverse transcription-quantitative polymerase chain reaction. Exosomes released by H827R cells (R/exo) may decrease the sensitivity of the human NSCLC HCC827 cell line to gefitinib. The results indicated that miR-21 expression was increased in R/exo and R/exo-treated H827S cells. However, miR-21 inhibition abrogated exosome-mediated drug resistance. Phosphorylated-protein kinase B (p-Akt), which is downstream of miR-21, was downregulated following gefitinib treatment; however, R/exo pretreatment elevated p-Akt levels and promoted the activation of Akt. By contrast, miR-21 inhibition reduced p-Akt expression. Therefore, the induction of miR-21 via exosomes and the activation of Akt may be mechanisms by which exosomes mediate the transfer of drug resistance.

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“…In addition, most, if not all, laboratory models of acquired resistance show continued activation of the AKT pathway despite TKI treatment. Thus, targeting AKT signaling may provide a rationale for novel therapeutic strategies to overcome EGFR-TKI resistance in NSCLC [44][45][46][47][48] . In this study, we present data showing that LC capilliposide can inhibit AKT activation and restore, at least partially, gefitinib sensitivity to NSCLC cells with acquired gefitinib resistance.…”

Section: Discussionmentioning

confidence: 99%

“…In this study, we present data showing that LC capilliposide can inhibit AKT activation and restore, at least partially, gefitinib sensitivity to NSCLC cells with acquired gefitinib resistance. In the presence of LC capilliposide, we [47,49,50] . Of note, our results also showed that exposure to LC capilliposide inhibits the activation of several other kinases, including WNK1, in gefitinib-treated PC-9-GR cells.…”

Section: Discussionmentioning

confidence: 99%

Capilliposide from Lysimachia capillipes inhibits AKT activation and restores gefitinib sensitivity in human non-small cell lung cancer cells with acquired gefitinib resistance

et al. 2016

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Most gefitinib-treated patients with non-small cell lung cancer (NSCLC) would eventually develop resistance. Lysimachia capillipes (LC) capilliposide extracts from LC Hemsl. show both in vitro and in vivo anti-cancer effects. In this study we investigated whether LC capilliposide in combination with gefitinib could overcome the resistance of NSCLC cells to gefitinib and identified the signaling pathways involved. Treatment with LC capilliposide alone inhibited the growth of a panel of NSCLC cell lines (PC-9, H460, H1975, H1299 and PC-9-GR) sensitive or resistant to gefitinib with IC 50 values in the range of μg/mL. In the gefitinib-resistant PC-9-GR cells (which have a T790M EGFR mutation), LC capilliposide (at the IC 30 , i.e. 1.2 μg/mL) markedly enhanced the inhibitory effects of gefitinib with its IC 50 value being decreased from 6.80±1.00 to 0.77±0.12 μmol/L. By using the median effect analysis we showed that combination treatment of LC capilliposide and gefitinib could restore gefitinib sensitivity in PC-9-GR cells. Furthermore, LC capilliposide (1.2 μg/mL) significantly increased the apoptotic responses to gefitinib (0.77 μmol/L) in PC-9-GR cells, but did not affect gefitinibinduced G 0 /G 1 arrest. Moreover, LC capilliposide (1.2 μg/mL) in combination with gefitinib (0.77, 1.0 μmol/L) markedly decreased the phosphorylation of the EGFR downstream signaling molecule AKT, which neither LC capilliposide nor gefitinib alone affected. In PC-9-GR cells with siRNA knockdown of AKT, addition of LC capilliposide was unable to increase gefitinib sensitivity. In a PC-9-GR xenograft mouse model, combination treatment with LC capilliposide (15 mg·kg -1 ·d -1, ip) and gefitinib (50 mg·kg -1 ·d -1, ip) dramatically enhanced tumor growth suppression (with a TGI of 109.3%), compared with TGIs of 22.6% and 56.6%, respectively, in mice were treated with LC capilliposide or gefitinib alone. LC capilliposide can restore the cells' sensitivity to gefitinib through modulation of pAKT levels, suggesting that a combination of LC capilliposide and gefitinib may be a promising therapeutic strategy to overcome gefitinib resistance in NSCLCs with a T790M mutation.

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Blocking the PI3K/AKT and MEK/ERK signaling pathways can overcome Gefitinib-resistance in non-small cell lung cancer cell lines

Cited by 79 publications

References 21 publications

MiR-130a Overcomes Gefitinib Resistance by Targeting Met in Non-Small Cell Lung Cancer Cell Lines

MiR-130a Overcomes Gefitinib Resistance by Targeting Met in Non-Small Cell Lung Cancer Cell Lines

Exosome‑mediated gefitinib resistance in lung cancer HCC827 cells via delivery of miR‑21

Capilliposide from Lysimachia capillipes inhibits AKT activation and restores gefitinib sensitivity in human non-small cell lung cancer cells with acquired gefitinib resistance

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