Analyzing the scaffold diversity of cyclin‐dependent kinase inhibitors and revisiting the clinical and preclinical pipeline

Cyclin-dependent kinase inhibitors (CDKi´s) display cytotoxic activity against different malignancies, including head and neck squamous cell carcinomas (HNSCC). By coordinating the DNA damage response, these substances may be combined with cytostatics to enhance cytotoxicity. Here, we investigated the influence of different CDKi´s (palbociclib, dinaciclib, THZ1) on two HNSCC cell lines in monotherapy and combination therapy with clinically-approved drugs (5-FU, Cisplatin, cetuximab). Apoptosis/necrosis, cell cycle, invasiveness, senescence, radiation-induced γ-H2AX DNA double-strand breaks, and effects on the actin filament were studied. Furthermore, the potential to increase tumor immunogenicity was assessed by analyzing Calreticulin translocation and immune relevant surface markers. Finally, an in vivo mouse model was used to analyze the effect of dinaciclib and Cisplatin combination therapy. Dinaciclib, palbociclib, and THZ1 displayed anti-neoplastic activity after low-dose treatment, while the two latter substances slightly enhanced radiosensitivity. Dinaciclib decelerated wound healing, decreased invasiveness, and induced MHC-I, accompanied by high amounts of surface-bound Calreticulin. Numbers of early and late apoptotic cells increased initially (24 h), while necrosis dominated afterward. Antitumoral effects of the selective CDKi palbociclib were weaker, but combinations with 5-FU potentiated effects of the monotherapy. Additionally, CDKi and CDKi/chemotherapy combinations induced MHC I, indicative of enhanced immunogenicity. The in vivo studies revealed a cell line-specific response with best tumor growth control in the combination approach. Global acting CDKi’s should be further investigated as targeting agents for HNSCC, either individually or in combination with selected drugs. The ability of dinaciclib to increase the immunogenicity of tumor cells renders this substance a particularly interesting candidate for immune-based oncological treatment regimens.

Download Full-text

Potential of Cyclin-Dependent Kinase Inhibitors as Cancer Therapy

ACS Medicinal Chemistry Letters ◽

10.1021/acsmedchemlett.1c00017 ◽

2021 ◽

Vol 12 (2) ◽

pp. 182-184

Author(s):

Ahmed F. Abdel-Magid

Keyword(s):

Cancer Therapy ◽

Kinase Inhibitors ◽

Cyclin Dependent Kinase

Download Full-text

Expression and mutational analysis of Cip/Kip family in early glottic cancer

The Journal of Laryngology & Otology ◽

10.1017/s0022215114003351 ◽

2015 ◽

Vol 129 (2) ◽

pp. 168-173 ◽

Cited By ~ 4

Author(s):

D-K Kim ◽

J H Lee ◽

O J Lee ◽

C H Park

Keyword(s):

Dna Methylation ◽

Polymerase Chain Reaction ◽

Kinase Inhibitors ◽

Mutational Analysis ◽

Glottic Cancer ◽

Cyclin Dependent Kinase ◽

Chain Reaction ◽

Single Strand Conformational Polymorphism ◽

Early Glottic Cancer ◽

Polymerase Chain

AbstractBackground:Genetic alteration of cyclin-dependent kinase inhibitors has been associated with carcinogenesis mechanisms in various organs.Objective:This study aimed to evaluate the expression and mutational analysis of Cip/Kip family cyclin-dependent kinase inhibitors (p21CIP1/WAF1, p27KIP1 and p57KIP2) in early glottic cancer.Methods:Expressions of Cip/Kip family and p53 were determined by quantitative reverse transcription polymerase chain reaction and densitometry. For the analysis of p21 inactivation, sequence alteration was assessed using single-strand conformational polymorphism polymerase chain reaction. Additionally, the inactivation mechanism of p27 and p57 were investigated using DNA methylation analysis.Results:Reduced expression of p27 and p57 were detected in all samples, whereas the expression of p21 was incompletely down-regulated in 6 of 11 samples. Additionally, single-strand conformational polymorphism polymerase chain reaction analysis showed the p53 mutation at exon 6. Methylation of p27 and p57 was detected by DNA methylation assay.Conclusion:Our results suggest that the Cip/Kip family may have a role as a molecular mechanism of carcinogenesis in early glottic cancer.

Download Full-text

Quo Vadis Advanced Prostate Cancer Therapy? Novel Treatment Perspectives and Possible Future Directions

Molecules ◽

10.3390/molecules26082228 ◽

2021 ◽

Vol 26 (8) ◽

pp. 2228

Author(s):

Jana Kvízová ◽

Vladimíra Pavlíčková ◽

Eva Kmoníčková ◽

Tomáš Ruml ◽

Silvie Rimpelová

Keyword(s):

Prostate Cancer ◽

Advanced Prostate Cancer ◽

Kinase Inhibitors ◽

Diagnostic Methods ◽

Common Disease ◽

Cyclin Dependent Kinase ◽

Future Directions ◽

Prostate Cancer Therapy ◽

Quo Vadis ◽

Antiandrogen Therapy

Prostate cancer is a very common disease, which is, unfortunately, often the cause of many male deaths. This is underlined by the fact that the early stages of prostate cancer are often asymptomatic. Therefore, the disease is usually detected and diagnosed at late advanced or even metastasized stages, which are already difficult to treat. Hence, it is important to pursue research and development not only in terms of novel diagnostic methods but also of therapeutic ones, as well as to increase the effectiveness of the treatment by combinational medicinal approach. Therefore, in this review article, we focus on recent approaches and novel potential tools for the treatment of advanced prostate cancer; these include not only androgen deprivation therapy, antiandrogen therapy, photodynamic therapy, photothermal therapy, immunotherapy, multimodal therapy, but also poly(ADP-ribose) polymerase, Akt and cyclin-dependent kinase inhibitors.

Download Full-text