Romidepsin induces G2/M phase arrest via Erk/cdc25C/cdc2/cyclinB pathway and apoptosis induction through JNK/c-Jun/caspase3 pathway in hepatocellular carcinoma cells

Sun, Weijian; Huang, He; He, Bin; Hu, Dan-Hong; Li, Pihong; Yu, Yaojun; Zhou, Xin; Lv, Zhen; Zhou, Lei; Hu, Tianye; Yao, Zhichao; Lu, Mingdong; Shen, Xian; Zheng, Zhiqiang

doi:10.1016/j.bcp.2016.12.008

Cited by 66 publications

(41 citation statements)

References 46 publications

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“…31 Some studies have reported that ERK-or JNK/MAPK activation induces G2/M phase arrest and apoptosis in solid tumors. [32][33][34][35][36] We found that palbociclib destabilizes HIF-1a and activates ERK1/2 under either normoxic or hypoxic conditions (Fig. 3).…”

Section: Discussionmentioning

confidence: 94%

The CDK4/6 inhibitor palbociclib synergizes with irinotecan to promote colorectal cancer cell death under hypoxia

et al. 2017

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Hypoxia is an inherent impediment to cancer therapy. Palbociclib, a highly selective inhibitor for CDK4/6, has been tested in numerous clinical trials and has been approved by the FDA. We previously reported that CDK inhibitors can destabilize HIF1a regardless of the presence of hypoxia and can sensitize tumor cells to TRAIL through dual blockade of CDK1 and GSK-3b. To translate this knowledge into a cancer therapeutic strategy, we investigated the therapeutic effects and molecular mechanisms of CDK inhibition against colon cancer cells under normoxia and hypoxia. We found that palbociclib sensitizes colon cancer cells to hypoxia-induced apoptotic resistance via deregulation of HIF-1a accumulation. In addition to inhibition of cell proliferation, we observed that palbociclib promotes colon cancer cell death regardless of the presence of hypoxia at a comparatively high concentration via regulating ERK/GSK-3b signaling and GSK-3b expression. Furthermore, palbociclib synergized with irinotecan in a variety of colon cancer cell lines with various molecular subtypes via deregulating irinotecan-induced Rb phosphorylation and reducing HIF-1a accumulation under normoxia or hypoxia. Collectively, our findings provide a novel combination therapy strategy against hypoxic colon cancer cells that may be further translated in the clinic.

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Section: Discussionmentioning

confidence: 94%

The CDK4/6 inhibitor palbociclib synergizes with irinotecan to promote colorectal cancer cell death under hypoxia

et al. 2017

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“…it has previously been reported that alT promotes apoptosis in osteosarcoma (28)(29)(30); therefore, the effect of alT on the expression levels on Bcl-2, Bax, cleaved caspase-3 and cleaved caspase-8, which all serve important roles in the process of apoptosis was explored. The expression levels of cleaved caspase-3 and cleaved caspase-8 were significantly upregulated in the alT-treated u2oS cells compared with the untreated cells ( Fig.…”

Section: Inhibitory Mechanisms Of Alt In Osteosarcoma Cellsmentioning

confidence: 99%

Alantolactone suppresses human osteosarcoma through the PI3K/AKT signaling pathway

et al. 2019

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osteosarcoma is the most common type of malignant bone cancer and results in cancer-related deaths among adolescents. alantolactone (alT) demonstrates antitumor properties in various diseases; however, its potential role in osteosarcoma is relatively unclear. The aim of the present study was to evaluate the effect of alT on osteosarcoma. alT significantly decreased the viability of U2OS and HOS osteosarcoma cell lines. Cells flow cytometry assay and Hoechst 33258 staining assay revealed that ALT significantly increased the proportion of apoptotic u2oS cells. in addition, wound healing and Transwell invasion assays demonstrated that the invasion and migration of osteosarcoma were markedly reduced upon alT treatment. it was hypothesized that the antitumor functions of alT are mediated through inhibition of the Pi3K/aKT signaling pathway. in conclusion, the results of the present study confirmed the inhibition of ALT on osteosarcoma cells via downregulation of Pi3K/aKT signaling pathways, suggesting alT as a potential therapeutic candidate for osteosarcoma.

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“…26 Therefore, Cdc2/cyclin B activity was inhibited and cells were arrested in G2/M phase. 25 In this study, we show that A-macB significantly induced NSCLC cell apoptosis through the ROS/p38 signaling pathway and delayed cells in G2/M phase by regulating the Chk1/2-Cdc25-Cdc2/cyclin B axis. The cytotoxic activity of A-macB was enhanced by the Chk1/2 inhibitor AZD7762.…”

Section: Introductionmentioning

confidence: 54%

“…17,23,24 An essential step in the cell cycle transition from G2 to mitosis includes the activation of the cell division cycle protein 2 (Cdc2)/cyclin B complex. 25 In response to DNA damage, checkpoint kinases 1 and 2 (Chk1 and Chk2) are activated to promote G2/M arrest via destruction or sequestration of Cdc25C phosphatases, preventing the reversal of the inhibitory phosphorylation of Cdc2 at Thr14 and Tyr15. 26 Therefore, Cdc2/cyclin B activity was inhibited and cells were arrested in G2/M phase.…”

Section: Introductionmentioning

confidence: 99%

Acetyl-macrocalin B, anent-kaurane diterpenoid, initiates apoptosis through the ROS-p38-caspase 9-dependent pathway and induces G2/M phase arrest via the Chk1/2-Cdc25C-Cdc2/cyclin B axis in non-small cell lung cancer

Wang

Zhang

Cao

et al. 2018

Cancer Biology & Therapy

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Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide, and novel effective drugs against NSCLC are urgently needed. Isodon species are rich in ent-kaurane diterpenoids that have been reported to have antitumor bioactivity. Acetyl-macrocalin B (A-macB) is a novel ent-kaurane diterpenoid isolated from Isodon silvatica, and its antitumor efficacy against NSCLC and the underlying mechanisms were scrutinized in depth. The viability of cells treated with A-macB was detected by CCK-8 and colony formation assays. Apoptosis and cell cycle distribution were analyzed by flow cytometry. The mechanisms were investigated by detecting ROS and performing western blotting and verification experiments with specific inhibitors. The in vivo effect of A-macB was explored in a nude mouse xenograft model. A-macB effectively inhibited H1299 and A549 cell viability, triggered apoptosis and delayed cells in the G2/M phase. A-macB induced cellular ROS production and then activated the p38 MAPK-mediated, caspase 9-dependent apoptotic pathway. Both the ROS scavenger NAC and the specific p38 inhibitor SB203580 inactivated the function of p38 induced by A-macB, thus preventing cells from apoptosis. A-macB activated the Chk1/2-Cdc25C-Cdc2/cyclin B1 axis to induce G2/M phase arrest. AZD7762 abrogated the function of Chk1/2, abolished the G2/M delay and enhanced the cytotoxicity of A-macB. Moreover, A-macB efficiently suppressed tumor growth in a mouse xenograft model without noticeable toxicity to normal tissues. Having both efficacy and relative safety, A-macB is a potential lead compound that is worthy of further exploration for development as an anticancer agent.

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Romidepsin induces G2/M phase arrest via Erk/cdc25C/cdc2/cyclinB pathway and apoptosis induction through JNK/c-Jun/caspase3 pathway in hepatocellular carcinoma cells

Cited by 66 publications

References 46 publications

The CDK4/6 inhibitor palbociclib synergizes with irinotecan to promote colorectal cancer cell death under hypoxia

The CDK4/6 inhibitor palbociclib synergizes with irinotecan to promote colorectal cancer cell death under hypoxia

Alantolactone suppresses human osteosarcoma through the PI3K/AKT signaling pathway

Acetyl-macrocalin B, anent-kaurane diterpenoid, initiates apoptosis through the ROS-p38-caspase 9-dependent pathway and induces G2/M phase arrest via the Chk1/2-Cdc25C-Cdc2/cyclin B axis in non-small cell lung cancer

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