Inhibition of Bcl-2 potentiates AZD-2014-induced anti-head and neck squamous cell carcinoma cell activity

Li, Yang; Cui, Jiangtao

doi:10.1016/j.bbrc.2016.06.100

Cited by 11 publications

(15 citation statements)

References 21 publications

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“…These compounds, including OSI-027 [25, 39], AZD-8055 [40], AZD-2014 [18, 28] and XL388 [41], directly inhibit mTOR kinase to block activity of both mTORC1 and mTORC2 [37, 38]. Here, we show that CZ415 blocked mTORC1 and mTORC2 activation, but failed to induce feedback AKT and ERK activation.…”

Section: Discussionmentioning

confidence: 92%

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Targeting mTOR by CZ415 Inhibits Head and Neck Squamous Cell Carcinoma Cells

Xie

Ding

et al. 2018

Cell Physiol Biochem

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Background/Aims: mTOR is an important therapeutic target for human head and neck squamous cell carcinoma (HNSCC). The current study tested the anti-HNSCC cell activity by a mTOR kinase inhibitor CZ415. Methods: HNSCC cells were treated with CZ415. Cell death was tested by lactate dehydrogenase (LDH) assay and MTT assay. Cell proliferation was tested by BrdU ELISA assay and [H³] thymidine incorporation assay, with apoptosis assayed by the TUNEL staining. A Western blotting assay was applied to test autophagy-associated proteins, mTOR and signalings. The nude mice xenograft model was established to study CZ415-mediated anti-tumor activity. Results: In established (SCC-9, SQ20B and A253 lines) and primary human HNSCC cells, CZ415 efficiently inhibited cell survival and proliferation. CZ415 blocked mTORC1/2 activation and inhibited ERK in HNSCC cells. CZ415 provoked feedback autophagy activation. Conversely, autophagy inhibitors (3-methyladenine and chloroquine) or Beclin-1 shRNA sensitized CZ415-induced HNSCC cell death. In vivo, CZ415 gavage inhibited SCC-9 tumor growth in nude mice, showing higher efficiency against Beclin-1-silenced tumors. Conclusion: CZ415 inhibits HNSCC cell growth in vitro and in vivo. Inhibition of autophagy can further sensitize CZ415 against HNSCC cells.

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Section: Discussionmentioning

confidence: 92%

“…As described [12], established HNSCC cell lines, SCC-9, SQ20B and A253, were from Dr. Cui’s group [18], and cells were maintained in FBS-containing DMEM medium [18]. …”

Section: Methodsmentioning

confidence: 99%

Targeting mTOR by CZ415 Inhibits Head and Neck Squamous Cell Carcinoma Cells

Xie

Ding

et al. 2018

Cell Physiol Biochem

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“…Based on the results above, we would speculate that Bcl-2 over-expression shall decrease PKC412's activity in CRC cells. Indeed, forced over-expression of Bcl-2 (Figure 5G), using a Bcl-2 expression vector ([20], see Methods), largely attenuated PKC412-induced viability reduction (Figure 5H) and apoptosis activation (Figure 5I) in HT-29 cells. These pharmacological and genetic evidences indicate that Bcl-2 could be a primary resistance factor of PKC412 in CRC cells.…”

Section: Resultsmentioning

confidence: 99%

“…The Bcl-2 expression construct in pSuper-puro plasmid was provided by Dr. Cui's group at Tianjin Medical University [20]. Lipofectamine 2000 was applied to transfect the Bcl-2 construct or the empty vector (pSuper-puro) to HT-29 cells.…”

Section: Methodsmentioning

confidence: 99%

Pre-clinical characterization of PKC412, a multi-kinase inhibitor, against colorectal cancer cells

Huang

et al. 2016

Oncotarget

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The potential effect of PKC412, a small molecular multi-kinase inhibitor, in colorectal cancer (CRC) cells was evaluated here. We showed that PKC412 was cytotoxic and anti-proliferative against CRC cell lines (HT-29, HCT-116, HT-15 and DLD-1) and primary CRC cells. PKC412 provoked caspase-dependent apoptotic death, and induced G2-M arrest in the CRC cells. AKT activation was inhibited by PKC412 in CRC cells. Reversely, expression of constitutively-active AKT1 (CA-AKT1) decreased the PKC412's cytotoxicity against HT-29 cells. We propose that Bcl-2 could be a primary resistance factor of PKC412. ABT-737, a Bcl-2 inhibitor, or Bcl-2 siRNA knockdown, dramatically potentiated PKC412's lethality against CRC cells. Forced Bcl-2 over-expression, on the other hand, attenuated PKC412's cytotoxicity. Significantly, PKC412 oral administration suppressed AKT activation and inhibited HT-29 tumor growth in nude mice. Mice survival was also improved with PKC412 administration. These results indicate that PKC412 may have potential value for CRC treatment.

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“…(1) Since the prevalence and mortality percentage of oral cancer have increased during the last 30 years and considering the irreversible damages and complications caused by this disease in patients and consequently in the society, screening methods which reveal the premalignant and malignant stages before the incidence of the visible lesion are of special importance. (1,2) Nowadays, with significant advances in immunology field and identification of different cytokines and other mediators of immune reactions, diagnostic tests such as Enzyme Linked Immune Assay (ELISA) have extremely high sensitivity and accuracy for tracing the cytokine in a very small sample surface. (3) Saliva is a suitable and accessible sample and most importantly, the sampling process doesn't cause any stress or inconvenience for subjects.…”

Section: Introductionmentioning

confidence: 99%

Comparison of the concentration of salivary IL8 in patients with oral squamous cell carcinoma and healthy subjects

Azizi

Dabirmoghadam

Keykha³

2016

J Res Dentomaxillofac Sci

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Background and Aim:Oral cancer is one of the most common cancers of the head and neck. Considering the high prevalence and mortality percentage of oral cancer and the significant advances in immunology and identification of different cytokines, the aim of the present study was to compare the concentration of IL8 in saliva of patients with oral squamous cell carcinoma (OSCC) and healthy subjects. Methods and Materials:In this case-control study, 20 individuals with a definite histopathology diagnosis of OSCC were selected as the case group and 20 healthy subjects were selected as the control group. The two groups were matched according to age, gender, cigarette smoking and alcohol consumption, medication consumption, periodontal disease (average CAL in first molars) and absence of systemic diseases. 5 ml of unstimulated whole saliva sample was collected with spitting method from each subject and the concentrations of salivary IL-8 were compared between the two groups. Linear regression and t-test were used for statistical analysis. Results: The concentration of IL-8 equaled 741.82±122.81 pg/ml in the case group and 341.25±83.52 pg/ml in the control group and t-test showed that the concentration of IL-8 in patients with OSCC is higher than that in the control subjects and this difference is significant. (p=0.049) According to regression equation, IL-8 has a significant correlation with tumor size index (T). (p=0.011) Conclusion: The results of this study showed that the concentrations of salivary IL-8 were significantly different between the patients with OSCC and healthy subjects (p=0.049) and the concentration of IL-8 has a significant correlation with tumor size (T).

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Inhibition of Bcl-2 potentiates AZD-2014-induced anti-head and neck squamous cell carcinoma cell activity

Cited by 11 publications

References 21 publications

Targeting mTOR by CZ415 Inhibits Head and Neck Squamous Cell Carcinoma Cells

Targeting mTOR by CZ415 Inhibits Head and Neck Squamous Cell Carcinoma Cells

Pre-clinical characterization of PKC412, a multi-kinase inhibitor, against colorectal cancer cells

Comparison of the concentration of salivary IL8 in patients with oral squamous cell carcinoma and healthy subjects

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