CCT128930 induces cell cycle arrest, DNA damage, and autophagy independent of Akt inhibition

Wang, Fengze; Chang, Zhengyao; Fei, Hong-rong; Yang, Mo; Yang, Xiaoyi; Sun, Bo

doi:10.1016/j.biochi.2014.04.008

Cited by 15 publications

(8 citation statements)

References 28 publications

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“…The unrestrained cell proliferation are the vital factor of tumor initiation and progression. Hence, the restriction of irregular cell multiplication signals was an promising approach to possess anticancer property ( Wang et al, 2014 ). The unrestricted proliferation and escaping from apoptosis are the crucial events that ultimately promotes the tumor progressions.…”

Section: Discussionmentioning

confidence: 99%

Dieckol exerts anticancer activity in human osteosarcoma (MG-63) cells through the inhibition of PI3K/AKT/mTOR signaling pathway

Zhang

Ren²,

Sun³

et al. 2021

Saudi Journal of Biological Sciences

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Background Osteosarcoma (OS) is the most common malignant bone cancer with more metastasis and increased occurrence in children and teen-agers and being responsible for more number of morbidity and mortality worldwide. Objective The current exploration was planned study the in vitro anticancer actions of dieckol against human OS MG-63 cells via PI3K/AKT/mTOR signaling inhibition. Methodology The cytotoxicity of dieckol was scrutinized by MTT assay. Effects of dieckol on the ROS accumulation, apoptotic cell death, and MMP level in the MG-63 cells were studied by respective fluorescence staining assays. The levels of proliferative, inflammatory, and apoptotic markers in the dieckol treated MG-63 cells were scrutinized by marker specific kits. The expressions of PI3K, AKT, and mTOR was assayed by RT-PCR. Results The MTT assay revealed that the dieckol dose dependently prevented MG-63 cells viability and the IC50 was found at 15 µM. Dieckol treatment effectively reduced the MMP level and improved the ROS generation and apoptosis in MG-63 cells. Dieckol also regulated the proliferative (cyclin D1), inflammatory (COX-2, IL-6, TNF-α, and NF-κB), and apoptotic (caspase-3, Bax, Bcl-2) markers in the MG-63 cells. The PI3K/AKT/mTOR signaling in the MG-63 cells were effectively inhibited by the dieckol treatment. Conclusion In conclusion, our findings from this study recommends that the dieckol could be a talented anticancer candidate for the OS management in the future.

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Section: Discussionmentioning

confidence: 99%

Dieckol exerts anticancer activity in human osteosarcoma (MG-63) cells through the inhibition of PI3K/AKT/mTOR signaling pathway

Zhang

Ren²,

Sun³

et al. 2021

Saudi Journal of Biological Sciences

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“…MK-2206 has been shown to augment the efficacy of chemotherapy drugs in ovarian cancer cells [35, 36]. The Akt2 inhibitor CCT-128930 has also been tested in cancer cell lines and resulted in cell cycle arrest, increased Annexin localization and autophagy markers, although these effects were seen at very high concentration of inhibitor [37]. Akt1-specific inhibitors have also been developed recently.…”

Section: Discussionmentioning

confidence: 99%

Akt isoform specific effects in ovarian cancer progression

et al. 2016

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Ovarian cancer remains a significant therapeutic problem and novel, effective therapies are needed. Akt is a serine-threonine kinase that is overexpressed in numerous cancers, including ovarian. Mammalian cells express three Akt isoforms which are encoded by distinct genes. Although there are several Akt inhibitors in clinical trials, most indiscriminately target all isoforms. Current in vitro data and animal knockout experiments suggest that the Akt isoforms may have divergent roles. In this paper, we determined the isoform-specific functions of Akt in ovarian cancer cell proliferation in vitro and in ovarian cancer progression in vivo. For in vitro experiments, murine and human ovarian cancer cells were treated with Akt inhibitors and cell viability was assessed. We used two different in vivo approaches to identify the roles of Akt isoforms in ovarian cancer progression and their influence on the primary tumor and tumor microenvironment. In one experiment, wild-type C57Bl6 mice were orthotopically injected with ID8 cells with stable knockdown of Akt isoforms. In a separate experiment, mice null for Akt 1-3 were orthotopically injected with WT ID8 cells (Figure 1). Our data show that inhibition of Akt1 significantly reduced ovarian cancer cell proliferation and inhibited tumor progression in vivo. Conversely, disruption of Akt2 increased tumor growth. Inhibition of Akt3 had an intermediate phenotype, but also increased growth of ovarian cancer cells. These data suggest that there is minimal redundancy between the Akt isoforms in ovarian cancer progression. These findings have important implications in the design of Akt inhibitors for the effective treatment of ovarian cancer.

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“…They also confirmed that BX795 in combination with AZD6244, an MEK inhibitor, increases apoptosis in AZD6244-resistant melanoma cells. Wang et al showed that CCT128930 increases the phosphorylation of AKT in HepG2 hepatoma cancer cells and that CCT128930 inhibits cell proliferation by inducing cell cycle arrest in G1 phase [ 31 ]. However, we found that BX795 did not inhibit the expression of pTBK1 (S172) and that CCT128930 did not inhibit the expression of pAKT (S473) at concentrations of 3.33 and 10 μM in HeyA8 and SKOV3 cells ( S2 Fig ).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Phospho-S6 Kinase, a Protein Involved in the Compensatory Adaptive Response, Increases the Efficacy of Paclitaxel in Reducing the Viability of Matrix-Attached Ovarian Cancer Cells

et al. 2016

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ObjectiveTo identify the proteins involved the compensatory adaptive response to paclitaxel in ovarian cancer cells and to determine whether inhibition of the compensatory adaptive response increases the efficacy of paclitaxel in decreasing the viability of cancer cells.MethodsWe used a reverse-phase protein array and western blot analysis to identify the proteins involved in the compensatory mechanism induced by paclitaxel in HeyA8 and SKOV3 ovarian cancer cells. We used a cell viability assay to examine whether inhibition of the proteins involved in the compensatory adaptive response influenced the effects of paclitaxel on cancer cell viability. All experiments were performed in three-dimensional cell cultures.ResultsPaclitaxel induced the upregulation of pS6 (S240/S244) and pS6 (S235/S236) in HeyA8 and SKOV3 cells, and pPRAS40 (T246) in HeyA8 cells. BX795 and CCT128930 were chosen as inhibitors of pS6 (S240/S244), pS6 (S235/S236), and pPRAS40 (T246). BX795 and CCT128930 decreased pS6 (S240/S244) and pS6 (S235/S236) expression in HeyA8 and SKOV3 cells. However, pPRAS40 (T246) expression was inhibited only by BX795 and not by CCT128930 in HeyA8 cells. Compared with paclitaxel alone, addition of BX795 or CCT128930 to paclitaxel was more effective in decreasing the viability of HeyA8 and SKOV3 cells.ConclusionAddition of BX795 or CCT128930 to inhibit pS6 (S240/S244) or pS6 (S235/S236) restricted the compensatory adaptive response to paclitaxel in HeyA8 and SKOV3 cells. These inhibitors increased the efficacy of paclitaxel in reducing cancer cell viability.

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CCT128930 induces cell cycle arrest, DNA damage, and autophagy independent of Akt inhibition

Cited by 15 publications

References 28 publications

Dieckol exerts anticancer activity in human osteosarcoma (MG-63) cells through the inhibition of PI3K/AKT/mTOR signaling pathway

Dieckol exerts anticancer activity in human osteosarcoma (MG-63) cells through the inhibition of PI3K/AKT/mTOR signaling pathway

Akt isoform specific effects in ovarian cancer progression

Inhibition of Phospho-S6 Kinase, a Protein Involved in the Compensatory Adaptive Response, Increases the Efficacy of Paclitaxel in Reducing the Viability of Matrix-Attached Ovarian Cancer Cells

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