Miltirone‑induced apoptosis in cisplatin‑resistant lung cancer cells through upregulation of p53 signaling pathways

Zhu, Zhaowei

doi:10.3892/ol.2018.8440

Cited by 8 publications

(9 citation statements)

References 26 publications

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“…Additionally, in vivo experimental HCC model revealed that treatment with miltirone significantly inhibited the HCC tumor growth. Our data concur with previous reports about the therapeutic potential of miltirone in cancer treatment 18 , 19 , 20 , 21 , 22 .…”

Section: Discussionsupporting

confidence: 93%

“…Apoptosis was generally considered as the predominant form of regulated cell death responsible for tumor therapies, a notion that was widely reported by numerous studies 40 , 41 . Miltirone used for cancer therapy attributed to its ability to inhibit cancer cell growth and to induce cancer cell apoptosis 19 , 20 , 21 . Zhou et al.…”

Section: Discussionmentioning

confidence: 99%

“…Miltirone triggered acute lymphoblastic leukemia cells apoptosis through reactive oxygen species (ROS)-generated breakdown of mitochondrial membrane potential (MMP) and DNA damage 20 . Moreover, it was reported that miltirone inhibited the growth of HCC cells and induced apoptosis in HepG2 cells 21 , 22 . These studies suggested that miltirone could be a potential agent for the treatment of cancer.…”

Section: Introductionmentioning

confidence: 99%

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Miltirone induces cell death in hepatocellular carcinoma cell through GSDME-dependent pyroptosis

Zhang

et al. 2020

Acta Pharmaceutica Sinica B

165

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Pyroptosis is a form of programmed cell death, and recently described as a new molecular mechanism of chemotherapy drugs in the treatment of tumors. Miltirone, a derivative of phenanthrene-quinone isolated from the root of Salvia miltiorrhiza Bunge, has been shown to possess anti-cancer activities. Here, we found that miltirone inhibited the cell viability of either HepG2 or Hepa1-6 cells, and induced the proteolytic cleavage of gasdermin E (GSDME) in each hepatocellular carcinoma (HCC) cell line, with concomitant cleavage of caspase 3. Knocking out GSDME switched miltirone-induced cell death from pyroptosis to apoptosis. Additionally, the induction effects of miltirone on GSDME-dependent pyroptosis were attenuated by siRNA-mediated caspase three silencing and the specific caspase three inhibitor Z-DEVD-FMK, respectively. Miltirone effectively elicited intracellular accumulation of reactive oxygen species (ROS), and suppressed phosphorylation of mitogen-activated and extracellular signal-regulated kinase (MEK) and extracellular regulated protein kinases 1/2 (ERK1/2) for pyroptosis induction. Moreover, miltirone significantly inhibited tumor growth and induced pyroptosis in the Hepa1-6 mouse HCC syngeneic model. These results provide a new insight that miltirone is a potential therapeutic agent for the treatment of HCC via GSDME-dependent pyroptosis.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Miltirone induces cell death in hepatocellular carcinoma cell through GSDME-dependent pyroptosis

Zhang

et al. 2020

Acta Pharmaceutica Sinica B

165

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“…The resistance of tumor cells to DDP allows cells to evade the cytotoxic effects of DDP, overcoming apoptosis (23); however, the underlying molecular mechanisms of DDP resistance require further investigation (24,25). miRNAs have been reported to be regulators of DDP resistance in NSCLC.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of miR‑3934‑5p enhances A549 cell sensitivity to cisplatin by targeting TP53INP1

2019

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Tumor protein p53-inducible nuclear protein 1 (TP53INP1) is a tumor suppressor associated with malignant tumor metastasis. In addition, it has been reported that hsa-microRNA (miR)-3934 serves key roles in various types of lung cancer, including small-cell lung carcinomas (SCLC) and non-SCLC (NSCLC). Therefore, the present study aimed to determine the effects of miR-3934-5p on cell proliferation and apoptosis, and on sensitivity to cisplatin (DDP). Reverse transcription-quantitative polymerase chain reaction analysis and western blotting were conducted for the analysis of mRNA and protein expression, respectively. Furthermore, the target of miR-3934-5p was investigated using a luciferase reporter assay and apoptosis was analyzed by flow cytometry. The results demonstrated that miR-3934-5p was upregulated in NSCLC tissues and A549 cells. Increases in the half-maximal inhibitory concentration (IC 50 ) and the expression of miR-3934-5p were observed in the A549/DDP group. miR-3934-5p mimic promoted the expression of miR-3934-5p and the IC 50 of the A549 cells. miR-3934-5p inhibitor downregulated miR-3934-5p and reduced the IC 50 of A549/DDP cells. miR-3934-5p was revealed to target the 3′-untranslated region of TP53INP1. The downregulation of miR-3934-5p significantly suppressed the proliferation and promoted the apoptosis of A549/DDP cells, which were reversed by transfection with TP53INP1 small interfering (si)RNA. The protein and mRNA expression levels of TP53INP1, B-cell lymphoma 2 (Bcl-2)-associated-X and p21 were significantly increased, whereas those of Bcl-2 were significantly decreased in the miR-3934-5p inhibitor group, which was significantly reduced by TP53INP1 siRNA transfection. miR-3934-5p, as a tumor suppressor in NSCLC, may promote the sensitivity of cells to DDP by targeting TP53INP1, associated with the suppression of cell proliferation and promotion of apoptosis.

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“…The results showed that compared with that of the control cells, the levels of S64 and S159 phosphorylation did not change significantly after the treatment with nicotine, while the phosphorylation of T163 was significantly enhanced. In the H1299 (Galluzzi et al, 2012;Zhu, 2018). The Mcl-1 protein is mainly localized to the mitochondrial outer membrane in the cells, but it has also been reported to be expressed in the nucleus.…”

Section: Nicotine Enhances the Viability Of H1299 Lung Cancer Cells By Enhancing The Phosphorylation Of The T163 Site Of Mcl-1mentioning

confidence: 99%

Nicotine induces cell survival and chemoresistance by stimulating Mcl‐1 phosphorylation and its interaction with Bak in lung cancer

Liu

Shi

Zhao

et al. 2019

Journal Cellular Physiology

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Nicotine is a major carcinogen in cigarettes, which can enhance cell proliferation and metastasis and increase the chemoresistance of cancer cells. Our previous data found that nicotine promotes cell survival in lung cancer by affecting the expression of antiapoptotic protein Mcl‐1, suggesting that the Mcl‐1 may be a therapeutic target for patients with lung cancer. In this study, we found that the effects of drug resistance on nicotine‐induced lung cancer cell lines were shown to influence the phosphorylation of Mcl‐1. Moreover, nicotine induces Mcl‐1 phosphorylation exclusively at the T163 site, which results in enhancement of the antiapoptotic activity of Mcl‐1 and increased cell survival. Meanwhile, nicotine can reduce the sensitivity of H1299 cells to CDDP via enhancement of the binding of Mcl‐1 to Bak, which inhibits the proapoptotic effect of Bak and ultimately leads to increased survival and drug resistance of lung cancer cells. Thus, nicotine‐induced cell survival and chemoresistance may occur in a mechanism by stimulating Mcl‐1 phosphorylation and its interaction with Bak, which may contribute to improving the efficacy of chemotherapy in the treatment of human lung cancer.

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Miltirone‑induced apoptosis in cisplatin‑resistant lung cancer cells through upregulation of p53 signaling pathways

Cited by 8 publications

References 26 publications

Miltirone induces cell death in hepatocellular carcinoma cell through GSDME-dependent pyroptosis

Miltirone induces cell death in hepatocellular carcinoma cell through GSDME-dependent pyroptosis

Downregulation of miR‑3934‑5p enhances A549 cell sensitivity to cisplatin by targeting TP53INP1

Nicotine induces cell survival and chemoresistance by stimulating Mcl‐1 phosphorylation and its interaction with Bak in lung cancer

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