An insight into the emerging role of cyclin-dependent kinase inhibitors as potential therapeutic agents for the treatment of advanced cancers

Chohan, Tahir Ali; Qayyum, Aisha; Rehman, Kanwal; Tariq, Muhammad; Akash, Muhammad Sajid Hamid

doi:10.1016/j.biopha.2018.08.116

Cited by 81 publications

(64 citation statements)

References 204 publications

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“…CDKs are positively regulated by cyclins (a, b, d and e), and negatively regulated by cyclin-dependent kinase inhibitors, such as p21 and p27. 15 After being activated in the G1 phase, CyclinD1 can phosphorylate pRb, which in turn promotes cells to progress to the S phase. 16 CyclinD1 plays an essential role in many cancers and cancer therapies.…”

Section: Discussionmentioning

confidence: 99%

<p>Hint1 Overexpression Inhibits the Cell Cycle and Induces Cell Apoptosis in Human Osteosarcoma Cells</p>

Duan¹,

Xie²,

Shi³

et al. 2020

OTT

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Background: New evidence suggests that histidine triad nucleotide-binding protein 1 (Hint1) exerts a tumor suppressor effect in various human tumors, such as colorectal cancer and gastric cancer. However, it has not been reported whether Hint1 is involved in the occurrence and development of osteosarcoma (OS). Materials and Methods: The present study investigated the role of Hint1 in human OS cells by using cell lines, including 143B, U2OS, KHOS-240S, Saos-2 and MG-63. Cell proliferation and apoptosis were detected by flow cytometry. Results: The present result revealed that Hint1 is downregulated in these cell lines. The overexpression of Hint1 by adenovirus transfection in 143B and MG63 cell lines suppressed the proliferation and cell cycle, and increased the cell apoptosis. Mechanically, it was found that Hint1 downregulated the cyclin D1 expression via FOXO1 inhibition. Furthermore, FOXO1 overexpression in the 143B and MG63 cell lines significantly blurred the effects of Hint1 on cellular proliferation and apoptosis. Conclusion: The present study indicates that Hint1 inhibits the development of OS by regulating FoxO1-cyclin D1, suggesting that Hint1 may be a new method for the treatment of OS.

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Section: Discussionmentioning

confidence: 99%

<p>Hint1 Overexpression Inhibits the Cell Cycle and Induces Cell Apoptosis in Human Osteosarcoma Cells</p>

Duan¹,

Xie²,

Shi³

et al. 2020

OTT

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“…Early CDK inhibitors developed were relatively nonspecific and often referred to as 'pan-CDK' inhibitors. Early drug discovery programs focused primarily on CDK2 inhibition as a target due to the observation of frequent dysregulation in a plethora of cancers subtypes [44,50]. Examples of first-generation inhibitors include flaviopiridol (alvocidib), olomucine, roscovitidine (seliciclib) and kenpaullone [44,51].…”

Section: First-generation Cdk Inhibitorsmentioning

confidence: 99%

“…Inhibition of CDK2 may offer a more appealing target, particularly in tumors such as melanoma, which may be driven by cyclin E amplification [44]. Alternatively, selectively targeting CDK7, CDK8 and CDK9, which are associated with basal transcription, may also prove a successful strategy as cancer cells frequently harbor unique vulnerabilities to selective suppression [50].…”

Section: Selective Cdk Inhibitorsmentioning

confidence: 99%

Advances in cyclin-dependent kinase inhibitors for the treatment of melanoma

Julve

Clark

Lythgoe

2020

Expert Opinion on Pharmacotherapy

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Introduction: Despite the recent advances in the treatment of malignant melanoma with immunotherapy and BRAF/MEK targeted agents, advanced disease still beholds a poor prognosis for a significant proportion of patients. Cyclin-dependent kinase (CDK) inhibitors have been investigated as novel melanoma therapeutics throughout a range of phase 1 and 2 trials, as single agents and in combination with established treatments. Areas covered: This article summarizes the rationale for, and development of CDK inhibitors in melanoma, with their evolution from pan-CDK inhibitors to highly specific agents, throughout clinical trials and finally their potential future use. Expert opinion: Whilst CDK inhibitors have been practice changing in breast cancer management, their efficacy is yet to be proven in melanoma. Combination with BRAF/MEK inhibitors has been hindered by dose-limiting toxicities, but their role may yet to be found within the spectrum of biomarker-derived personalized melanoma management. The effect that CDK inhibitors can have as an adjunct to immunotherapy also remains to be seen.

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“…Since several different factors may lead to malignancy; targeting cancer cells without harming normal cells has remained to be a challenging task for pharmaceutical scientists ( Chohan et al, 2015 ). Conventional modalities such as surgical removal, hormonal therapy, immune therapy, radiotherapy and chemotherapy for cancer treatment has inadequate ability to discriminate between the normal and cancerous cells ( Chohan et al, 2018 ); hence, causing unacceptable toxicities with modest therapeutic benefits. Alternatively, the natural products from plant kingdom offer protective and therapeutic actions to all cells with low cytotoxicity ( Safarzadeh et al, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

Phytochemical profiling, antioxidant and antiproliferation potential of Euphorbia milii var.: Experimental analysis and in-silico validation

Chohan

Sarfraz

Rehman

et al. 2020

Saudi Journal of Biological Sciences

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This study was aimed to investigate the anticancer potential of Euphorbia milii ( E. milii ) using an exquisite combination of phytopharmacological and advanced computational techniques. The chloroform fraction (Em-C) of E. milii methanol extract showed the highest antioxidant activity (IC 50 : 6.41 ± 0.99 µg/ml) among all studied fractions. Likewise, Em-C also showed significant cytotoxicity (IC 50 : 11.2 ± 0.8 µg/ml) when compared with that of standard compound 5-fluorouracil (5-FU) (IC 50 : 4.22 ± 0.6 µg/ml) against hepatocarcinoma cell line (HepG2). However, in a human cervical cancer cell line (HeLa), Em-C demonstrated a non-significant difference in cytotoxicity (22.1 ± 0.8 µg/ml) when compared with that of 5-FU (IC 50 : 6.87 ± 0.5 µg/ml). Furthermore, Western blot and qRT-PCR analysis revealed that the suppression of HepG2 cells was the consequence of a tremendous decrease in CDK2 and E2F1 protein expression. The GC–MS analysis of Em-C revealed the unique presence of cyclobarbital (CBT) and benzodioxole derivative (BAN) as major constituents. Furthermore, molecular docking of compounds BAN, CBT, and MBT into the binding site of different molecular targets i.e. cyclin dependent kinase 2 (CDK2), thymidylate synthase (TS), caspase 3, BCL2 and topoisomerase II was carried out. Compounds BAN and CBT have demonstrated remarkable binding affinity towards CDK2 and thymidylate synthase, respectively. Molecular dynamic simulation studies have further confirmed the finding of docking analysis, suggesting that CDK2 and TS can act as an attractive molecular target for BAN and CBT, respectively. It can be concluded that these E. milii phytoconstituents (BAN and CBT) may likely be responsible for anti-invasive activity against HepG2 cells.

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An insight into the emerging role of cyclin-dependent kinase inhibitors as potential therapeutic agents for the treatment of advanced cancers

Cited by 81 publications

References 204 publications

<p>Hint1 Overexpression Inhibits the Cell Cycle and Induces Cell Apoptosis in Human Osteosarcoma Cells</p>

<p>Hint1 Overexpression Inhibits the Cell Cycle and Induces Cell Apoptosis in Human Osteosarcoma Cells</p>

Advances in cyclin-dependent kinase inhibitors for the treatment of melanoma

Phytochemical profiling, antioxidant and antiproliferation potential of Euphorbia milii var.: Experimental analysis and in-silico validation

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