Tanshinone IIA combined with cisplatin synergistically inhibits non‐small‐cell lung cancer in vitro and in vivo via down‐regulating the phosphatidylinositol 3‐kinase/Akt signalling pathway

Liao, Xiao‐Zhong; Gao, Ying; Huang, Sheng; Chen, Zhuang‐Zhong; Sun, Lingling; Liu, Jiahui; Chen, Hanrui; Yu, Liguo; Zhang, Jiaxing; Lin, Lizhu

doi:10.1002/ptr.6392

Cited by 50 publications

(32 citation statements)

References 32 publications

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“…9,30,31 In the past decades, Tan IIA has attracted great interest in cancer prevention and chemotherapy due to its significant antitumor efficacy and minimal side effects. Recent reports revealed that Tan IIA inhibits NSCLC cells via down-regulating the PI3K/Akt signalling 32 and activating the JNK pathway. 33 Although the induction of mitochondrial apoptosis is involved in Tan IIA-mediated antitumor activity, the molecular mechanism was not clear.…”

Section: Discussionmentioning

confidence: 99%

<p>Inhibition of EGFR Signaling and Activation of Mitochondrial Apoptosis Contribute to Tanshinone IIA-Mediated Tumor Suppression in Non-Small Cell Lung Cancer Cells</p>

Gao

Liu

et al. 2020

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Background: Deregulation of epidermal growth factor receptor (EGFR) signaling plays a critical role in non-small cell lung cancer (NSCLC) tumorigenesis. The natural product Tanshinone IIA (Tan IIA) exhibits significant anti-tumor effect in various human cancers, however, the mechanism remains elusive. Methods: The inhibitory effect of Tan IIA NSCLC cells was determined by MTS and soft agar assays. The activation of EGFR signaling and the protein level of myeloid cell leukemia 1 (Mcl-1) were examined by immunoblot (IB), immunohistochemical staining (IHC), and ubiquitination analysis. The in vivo anti-tumor effect was validated by the xenograft mouse model. Results: Tan IIA inhibits NSCLC cells through suppression of EGFR signaling. Tan IIA decreases cell viability and colony formation in EGFR wild type and activating mutant cell lines. The IB data further confirmed that Tan IIA suppresses EGFR phosphorylation timeand dose-dependently. Tan IIA destabilizes Mcl-1 and shortens the half-life. Ubiquitination analysis showed that treatment with Tan IIA promotes Mcl-1 ubiquitination and degradation. Further study showed that the downregulation of EGFR-Akt signaling is required for Tan IIA-induced Mcl-1 reduction. Ectopic overexpression of constitutively activated Akt1 compromised these antitumor efficacies in Tan IIA-treated NSCLC cells. Finally, Tan IIA inhibited the in vivo tumor growth. Conclusion: Our data indicate that Tan IIA acts as an EGFR signaling inhibitor, and targeting EGFR-Akt-Mcl1 axis could provide a new option for NSCLC treatment.

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Section: Discussionmentioning

confidence: 99%

<p>Inhibition of EGFR Signaling and Activation of Mitochondrial Apoptosis Contribute to Tanshinone IIA-Mediated Tumor Suppression in Non-Small Cell Lung Cancer Cells</p>

Gao

Liu

et al. 2020

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“…Taken together, these results indicate that the combination of cordycepin and cDDP has a synergistic effect on inhibiting apoptosis. Other studies have shown that cordycepin can inhibit the invasion and metastasis of cancer cells 29 – 32 . Meanwhile, through our research, we found that cordycepin and cDDP can synergistically inhibit the ability of esophageal cancer cells to invade and metastasize and associate with EMT.…”

Section: Discussionmentioning

confidence: 92%

Cordycepin enhances the chemosensitivity of esophageal cancer cells to cisplatin by inducing the activation of AMPK and suppressing the AKT signaling pathway

et al. 2020

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Although cisplatin (cDDP), is a first-line chemotherapy drug for esophageal cancer, it still has the potential to develop drug resistance and side effects. There is increasing evidence that cordycepin can work synergistically with other chemotherapy drugs. Therefore, we investigated whether combination therapy of cordycepin and cDDP may enhance the therapeutic effect of cDDP. We performed a series of functional tests to study the effect of medical treatment on esophageal cancer cells. We then used GO analysis to examine the pathways affected by treatment with cordycepin and cDDP. Next, we observed changes in the abundance of the selected pathway proteins. The in vivo animal model supported the results of the in vitro experiments. Co-treatment with cordycepin and cDDP inhibited cell growth, migration, and metastasis, as well as induced apoptosis. Cordycepin was found to effectively enhance activation of AMPK and inhibited activity of AKT. In all treatment groups, the expression levels of p-PI3K, p-Akt, p-p70S6K, Caspase-3, and Bcl-2 were significantly reduced, while the expression levels of p-AMPK, cleaved Caspase-3, and Bax increased, and the total levels of Akt, PI3K, and p70S6K levels remained unchanged. Overall, cordycepin was found to enhance the chemical sensitivity of esophageal cancer cells to cisplatin by inducing AMPK activation and inhibiting the AKT signaling pathway. Combination therapy of cordycepin and cisplatin represent a novel potential treatment of esophageal cancer.

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“…Treatment with Tan IIA induced cell cycle arrest, impaired angiogenesis, invasion, and metastasis, and promoted apoptosis (34). Furthermore, Tan IIA enhanced the tumor-killing effect when combined with chemotherapy agents or radiotherapy (40,41). A panel of protein kinases has been demonstrated as potential targets in Tan IIA-treated tumor cells, such as PI3K/Akt, MAPK, and mTOR (41)(42)(43).…”

Section: Discussionmentioning

confidence: 99%

Targeting Aurora B kinase with Tanshinone IIA Suppresses Tumor Growth and Overcomes Radioresistance

Gao

liu

et al. 2020

Preprint

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Background Aurora B kinase is aberrantly overexpressed in various tumors and shown to be a promising target for anti-cancer therapy. Methods A customized natural product library was used for natural compound screening through Molecular modeling. The expression of Aurora B in oral squamous cell carcinoma (OSCC) and the inhibitory effect of Tanshinone IIA (Tan IIA) on OSCC were examined by MTS and colony formation assays, immunoblot, immunofluorescence, immunohistochemical staining, and in vivo xenograft experiment. Results Aurora B is overexpressed in OSCC tumor tissues and cell lines. Knockdown of Aurora B inhibited the malignant phenotypes of OSCC cells in vitro and in vivo. With a molecular modeling screening of 74 commercially available natural products, we identified that Tan IIA, as a potential Aurora B kinase inhibitor. Tan IIA exhibited a significant anti-tumor effect on OSCC cells both in vitro and in vivo, including reduction of Aurora B and histone H3 phosphorylation, induction of G2/M cell cycle arrest, increase the population of polyploid cells, and promotion of apoptosis. The in vivo mouse model revealed that Tan IIA delayed tumor growth of OSCC cells. Tan IIA alone or in combination with radiation overcame radioresistance in OSCC xenograft tumors. Conclusion Our data indicates that targeting Aurora B kinase signaling is a promising anti-tumor strategy for OSCC treatment.

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Tanshinone IIA combined with cisplatin synergistically inhibits non‐small‐cell lung cancer in vitro and in vivo via down‐regulating the phosphatidylinositol 3‐kinase/Akt signalling pathway

Cited by 50 publications

References 32 publications

<p>Inhibition of EGFR Signaling and Activation of Mitochondrial Apoptosis Contribute to Tanshinone IIA-Mediated Tumor Suppression in Non-Small Cell Lung Cancer Cells</p>

<p>Inhibition of EGFR Signaling and Activation of Mitochondrial Apoptosis Contribute to Tanshinone IIA-Mediated Tumor Suppression in Non-Small Cell Lung Cancer Cells</p>

Cordycepin enhances the chemosensitivity of esophageal cancer cells to cisplatin by inducing the activation of AMPK and suppressing the AKT signaling pathway

Targeting Aurora B kinase with Tanshinone IIA Suppresses Tumor Growth and Overcomes Radioresistance

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