The cyclin-dependent kinase inhibitor flavopiridol (alvocidib) inhibits metastasis of human osteosarcoma cells

Zocchi, Loredana; Wu, Stephanie; Wu, Jie; Hayama, Ken

doi:10.18632/oncotarget.25239

Cited by 38 publications

(16 citation statements)

References 37 publications

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“…A more recent study has revealed that treatment of MYC-amplified and CDK9 overexpressing patient-derived tumor xenografts (PDTX) osteosarcoma mouse models, with a multi-CDK inhibitor, resulted in decreased tumor growth [56]. Similar results have been demonstrated with the multi-CDK inhibitor, Flavopiridol, targeting CDK1, 2, 6, 7 and 9, which decreases metastasis and cell survival in osteosarcomas [57]. Recently, another novel highly selective CDK9 inhibitor, MC180295, shown broad anti-cancer activity in vitro and demonstrated efficacy against lung cancer in vivo [25].…”

Section: Discussionmentioning

confidence: 79%

Cyclin-dependent kinase 9 (CDK9) is a novel prognostic marker and therapeutic target in osteosarcoma

Seebacher

Hornicek

et al. 2019

EBioMedicine

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Background Cyclin-dependent protein kinase 9 (CDK9) has been shown to play an important role in the pathogenesis of malignant tumors. However, the expression and function of CDK9 remain unknown in osteosarcomas. The purpose of this study is to assess the expression, function and clinical prognostic relationship of CDK9 in osteosarcomas. Methods A tissue microarray of 70 patient specimens was analyzed by immunohistochemistry to measure CDK9 expression, which was further investigated for correlation with patient clinical characteristics. CDK9 expression in osteosarcoma cell lines and patient tissues was also evaluated by Western blotting. CDK9-specific siRNA and the CDK9 inhibitor were applied to determine the effect of CDK9 inhibition on osteosarcoma cell proliferation and anti-apoptotic activity. The clonogenicity and migration activity were also examined using clonogenic and wound healing assays. A 3D cell culture model was performed to mimic the in vivo osteosarcoma environment to further validate the effect of CDK9 inhibition on osteosarcoma cells. Findings We demonstrated that higher CDK9-expression is associated with significantly shortened patient survival by immunohistochemistry. Expression of CDK9 is inversely correlated to the percent of tumor necrosis post-neoadjuvant chemotherapy, which is the most important predictive factor of disease outcome for osteosarcoma patients. Knockdown of CDK9 with siRNA and inhibition of CDK9 activity with inhibitor decreased cell proliferation and induced apoptosis in osteosarcoma. Interpretation High expression of CDK9 is an independent predictor of poor prognosis in osteosarcoma patients. Our results suggest that CDK9 is a novel prognostic marker and a promising therapeutic target for osteosarcomas.

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Section: Discussionmentioning

confidence: 79%

Cyclin-dependent kinase 9 (CDK9) is a novel prognostic marker and therapeutic target in osteosarcoma

Seebacher

Hornicek

et al. 2019

EBioMedicine

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“…Moreover, the anti-proliferative and pro-apoptotic effects of the flavopiridol in combination with oxaliplatin in melanoma cells and its subcutaneously injected allograft were associated with enhanced caspase -3, -7 and -9 activities in a dose dependent manner via the mitochondrial apoptotic pathway [174]. In metastatic osteosarcoma U2OS, SaOS-2, SJSA-1, and 143B, at nanomolar concentrations flavopiridol treatment led to significant reduction of cadherin 3 and 4, thus reducing metastatic potential in lungs [175].…”

Section: Phytochemicalsmentioning

confidence: 99%

Flavonoids in Cancer and Apoptosis

Abotaleb

Samuel

Varghese

et al. 2018

Cancers

532

394

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Cancer is the second leading cause of death globally. Although, there are many different approaches to cancer treatment, they are often painful due to adverse side effects and are sometimes ineffective due to increasing resistance to classical anti-cancer drugs or radiation therapy. Targeting delayed/inhibited apoptosis is a major approach in cancer treatment and a highly active area of research. Plant derived natural compounds are of major interest due to their high bioavailability, safety, minimal side effects and, most importantly, cost effectiveness. Flavonoids have gained importance as anti-cancer agents and have shown great potential as cytotoxic anti-cancer agents promoting apoptosis in cancer cells. In this review, a summary of flavonoids and their effectiveness in cancer treatment targeting apoptosis has been discussed.

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“…Scratch-wound assay was performed as previously described [ 44 ]. Cells (1 × 10 6 /well) were plated on 6-well plates.…”

Section: Methodsmentioning

confidence: 99%

Chromatin remodeling protein HELLS is upregulated by inactivation of the RB-E2F pathway and is nonessential for osteosarcoma tumorigenesis

2018

Oncotarget

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Osteosarcoma is the most common primary bone malignancy in children and adolescents. Among the various molecular mechanisms implicated in osteosarcomagenesis, the RB-E2F pathway is of particular importance as virtually all cases of osteosarcoma display alterations in the RB-E2F pathway. In this study, we examined the transcription factor E2F family members that are associated with increased malignancy in Rb1-null osteosarcoma tumors. Using genetically engineered mouse models of osteosarcoma, we found that loss of activator E2Fs, E2F1 and E2F3, significantly delays tumor progression and increases the overall survival of the p53/Rb1-deficient osteosarcoma mouse model. We also studied the role of helicase, lymphoid specific (HELLS), a chromatin remodeling protein identified as a critical downstream effector of the RB-E2F signaling pathway in various cancers. In this study, we confirmed that the RB-E2F pathway directly regulates HELLS gene expression. We also found that HELLS mRNA is upregulated and its protein overexpressed in osteosarcoma. Using loss-of-function assays to study the role of HELLS in human osteosarcoma, we observed that HELLS has no effect on tumor proliferation and migration. Further, we pioneered the study of Hells in developmental tumor models by generating Hells conditional knockout osteosarcoma mouse models to examine the role of HELLS in osteosarcoma tumor development. We found that loss of Hells in osteosarcoma has no effect in tumor initiation and overall survival of mice. This suggests that while HELLS may serve as a biomarker for tumorigenesis and for RB-E2F pathway status, it is unlikely to serve as a relevant target for therapeutics in osteosarcoma.

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The cyclin-dependent kinase inhibitor flavopiridol (alvocidib) inhibits metastasis of human osteosarcoma cells

Cited by 38 publications

References 37 publications

Cyclin-dependent kinase 9 (CDK9) is a novel prognostic marker and therapeutic target in osteosarcoma

Cyclin-dependent kinase 9 (CDK9) is a novel prognostic marker and therapeutic target in osteosarcoma

Flavonoids in Cancer and Apoptosis

Chromatin remodeling protein HELLS is upregulated by inactivation of the RB-E2F pathway and is nonessential for osteosarcoma tumorigenesis

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