Roscovitine effectively enhances antitumor activity of temozolomide in vitro and in vivo mediated by increased autophagy and Caspase-3 dependent apoptosis

Pandey, Vimal; Ranjan, Nikhil; Narne, Parimala; Babu, Phanithi Prakash

doi:10.1038/s41598-019-41380-1

Cited by 29 publications

(26 citation statements)

References 41 publications

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“…Resistance to TRAIL-mediated apoptosis in GBM was overcome by roscovitine's ability to downregulate survivin, XIAP and Mcl-1 [97,98] . More recently, using glioma cell lines and an in vivo orthotopic glioma model, the combination of roscovitine with TMZ was shown to result in increased autophagy and caspase-3 mediated cell death [99] . Menn et al [100] showed the ability of roscovitine to cross the BBB in healthy adult rats while studying ischemic stroke.…”

Section: Ckis In Glioma Treatment -Preclinical Studiesmentioning

confidence: 99%

Cyclin-dependent kinase inhibitors in brain cancer: current state and future directions

Juric¹,

Murphy²

2020

CDR

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Cyclin-dependent kinases (CDKs) are important regulatory enzymes in the normal physiological processes that drive cell-cycle transitions and regulate transcription. Virtually all cancers harbour genomic alterations that lead to the constitutive activation of CDKs, resulting in the proliferation of cancer cells. CDK inhibitors (CKIs) are currently in clinical use for the treatment of breast cancer, combined with endocrine therapy. In this review, we describe the potential of CKIs for the treatment of cancer with specific focus on glioblastoma (GBM), the most common and aggressive primary brain tumour in adults. Despite intense effort to combat GBM with surgery, radiation and temozolomide chemotherapy, the median survival for patients is 15 months and the majority of patients experience disease recurrence within 6-8 months of treatment onset. Novel therapeutic approaches are urgently needed for both newly diagnosed and recurrent GBM patients. In this review, we summarise the current preclinical and clinical findings emphasising that CKIs could represent an exciting novel approach for GBM treatment.

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Section: Ckis In Glioma Treatment -Preclinical Studiesmentioning

confidence: 99%

Cyclin-dependent kinase inhibitors in brain cancer: current state and future directions

Juric¹,

Murphy²

2020

CDR

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“…Inhibiting Cdk5 in glioma cells (either in vivo or in vitro) increases the rate of autophagy and of caspase-3-dependent apoptosis. Co-treatment with RSV plus TMZ prevented the glioma growth, reduced angiogenesis, and limited tumor dissemination by reducing the number of reactive astrocytes [209].…”

Section: The Standard Care: Temozolomidementioning

confidence: 94%

“…Inhibition of Cdk5 increase autophagy and apoptosis dependent of caspase-3; decreases the levels of Ki67, GFAP, VEGF, and CD31; reduces tumor progression by decreasing reactive astrocytes surrounding the glioma [209].…”

Section: Roscovitine (Cyclin-dependent Kinase Cdk Inhibitor)mentioning

confidence: 99%

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Autophagy as a Potential Therapy for Malignant Glioma

et al. 2020

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Glioma is the most frequent and aggressive type of brain neoplasm, being anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM), its most malignant forms. The survival rate in patients with these neoplasms is 15 months after diagnosis, despite a diversity of treatments, including surgery, radiation, chemotherapy, and immunotherapy. The resistance of GBM to various therapies is due to a highly mutated genome; these genetic changes induce a de-regulation of several signaling pathways and result in higher cell proliferation rates, angiogenesis, invasion, and a marked resistance to apoptosis; this latter trait is a hallmark of highly invasive tumor cells, such as glioma cells. Due to a defective apoptosis in gliomas, induced autophagic death can be an alternative to remove tumor cells. Paradoxically, however, autophagy in cancer can promote either a cell death or survival. Modulating the autophagic pathway as a death mechanism for cancer cells has prompted the use of both inhibitors and autophagy inducers. The autophagic process, either as a cancer suppressing or inducing mechanism in high-grade gliomas is discussed in this review, along with therapeutic approaches to inhibit or induce autophagy in pre-clinical and clinical studies, aiming to increase the efficiency of conventional treatments to remove glioma neoplastic cells.

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“…Cyclin-dependent kinase-5(Cdk-5), a threonine or serine kinaseis overexpressed in glioma cells in comparison to the healthy human astrocytes is responsible for neuronal dysfunction and death [198]. Pandey (2019) reported both in vitro and in vivo enhancement of the antitumour activity of temozolomide (TMZ) by the drug Roscovitine (RSV) known to inhibit Cdk-5 [199,200]. This is an interesting result since use of TMZ alone is not effective for gliomas after a while due to the development of drug resistance by malignant cells.…”

Section: Drug Repurposing For Cancermentioning

confidence: 99%

Exploring the new horizons of drug repurposing: A vital tool for turning hard work into smart work

Kumar

Harilal

Gupta

et al. 2019

European Journal of Medicinal Chemistry

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a b s t r a c tDrug discovery and development are long and financially taxing processes. On an average it takes 12e15 years and costs 1.2 billion USD for successful drug discovery and approval for clinical use. Many lead molecules are not developed further and their potential is not tapped to the fullest due to lack of resources or time constraints. In order for a drug to be approved by FDA for clinical use, it must have excellent therapeutic potential in the desired area of target with minimal toxicities as supported by both pre-clinical and clinical studies. The targeted clinical evaluations fail to explore other potential therapeutic applications of the candidate drug. Drug repurposing or repositioning is a fast and relatively cheap alternative to the lengthy and expensive de novo drug discovery and development. Drug repositioning utilizes the already available clinical trials data for toxicity and adverse effects, at the same time explores the drug's therapeutic potential for a different disease. This review addresses recent developments and future scope of drug repositioning strategy.

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Roscovitine effectively enhances antitumor activity of temozolomide in vitro and in vivo mediated by increased autophagy and Caspase-3 dependent apoptosis

Cited by 29 publications

References 41 publications

Cyclin-dependent kinase inhibitors in brain cancer: current state and future directions

Cyclin-dependent kinase inhibitors in brain cancer: current state and future directions

Autophagy as a Potential Therapy for Malignant Glioma

Exploring the new horizons of drug repurposing: A vital tool for turning hard work into smart work

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