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Garcinia indica (Kokum) and Ilex aquifolium (European Holly)
Published in Azamal Husen, Herbs, Shrubs, and Trees of Potential Medicinal Benefits, 2022
Dicson Sheeja Malar, Mani Iyer Prasanth, Tewin Tencomnao, James Michael Brimson, Anchalee Prasansuklab
Garcinol exhibited morphological changes and inhibited the proliferation of human non-small cell lung carcinoma (NSCLC) cells. Garcinol induced G1 cell cycle arrest was mediated through the upregulation of CDK inhibitors p21Waf1/Cip1 and p27KIP1. Moreover, cyclin-dependent kinase 2 (CDK2), cyclin-dependent kinase 4 (CDK4), cyclin D1, and cyclin D3 were decreased, whereas cyclin E and cyclin-dependent kinase 6 (CDK6) were increased along with inhibition of ERK and p38-MAPK (Yu et al., 2014). In A549 cells, garcinol enriched DNA damage-inducible transcript 3 (DDIT3), altered DDIT3-CCAAT-enhancer-binding proteins beta (C/EBPβ) interaction resulting in the attenuation of the prognostic cancer cell marker Aldehyde Dehydrogenase 1 Family Member A1 (ALDH1A1) expression (Wang et al., 2017a). In addition, garcinol significantly diminished the ability of the NSCLC cells to form spheres and form colonies, by impairing phosphorylation of LRP6, a co-receptor of Wnt and STAT3, downregulating β-catenin, Dvl2, Axin2, and cyclin D1 expressions, suggesting its ability to regulate the Wnt/β-catenin signaling pathway (Huang et al., 2018). Garcinol induced the sensitivity of A549 cells toward TRAIL and induced apoptosis mediated through upregulation of DR5 and downregulation c-FLIP (Kim et al., 2018).
Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Ribociclib (KisqaliTM), developed by Novartis and Astex Pharmaceuticals, is an inhibitor of CDK4 and CDK6, with some activity against Cyclin D3 (Figure 6.76). In 2017 it gained FDA and EMA approval for use in combination with an aromatase inhibitor such as letrozole to treat HR-positive/HER2-negative advanced or metastatic breast cancers. It is also recommended by NICE in the UK for this indication. Structure of ribociclib (KisqaliTM).
Familial Multiple Myeloma
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
IgH translocations involving the immunoglobulin heavy chain (IgH) locus on chromosome 14q32 (IgH translocated multiple myeloma) are found in 30% of cases, and are due to errors of IgH switch recombination and somatic hypermutation resulting in the juxtaposition of IgH gene sequences located at chromosome 14q32 with non-immunoglobulin DNA loci of 11q13, 4p16.3, 16q23, 20q11, and 6p21. Specifically, t(11;14)(q13;q32) leads to the dysregulation of CCND1 (cyclin D1, which is responsible for 15% of cases); t(4;14)(p16;q32) puts oncogenes FGFR3 and MMSET under control of the IgH gene locus and increases the expression of cyclin D2 (6% of cases); t(14;16)(q32;q23) and t(14;20)(q32;q11) also bring oncogenes C-MAF and MAFB within the IgH gene locus and enhance cyclin D2 expression (representing 4% and <1% of cases, respectively), and t(6;14)(p21;q32) as well as other IgH translocations contributes to the increased expression of CCND3 (cyclin D3, 5% of cases) [1,2].
Advances in cyclin-dependent kinase inhibitors for the treatment of melanoma
Published in Expert Opinion on Pharmacotherapy, 2021
Maximilian Julve, James J. Clark, Mark P. Lythgoe
Specifically, in melanoma several trials are underway which explore the use of CDK 4/6i with concomitant use of exploratory biomarkers. The LOGIC (NCT01820364) & LOGIC-2 (NCT02159066) trials utilizes an adaptive trial design which focuses on BRAFv600 mutant melanoma patients who have progressed on encorafenib and binimetinib. This drug combination is continued beyond progression with a third agent added based on tumor molecular phenotyping, including ribociclib, buparlisib (phosphoinositide-3-kinase inhibitor), infigratinib (fibroblast growth factor receptor inhibitor) or capmatinib (MET inhibitor). The LOGIC trial has been terminated due to scientific and business considerations, however LOGIC 2 is still recruiting at the date of censoring. A further clinical trial based on molecular profiling and matched targeted therapy, called MatchMel (NCT02645149) is underway for patients with melanoma and BRAF or NRAS mutations. This includes palbociclib as a potential therapy, in addition to other targeted therapies for patients with abnormalities in cyclin D1, cyclin D3 and p16INK4A.
Investigation of TF-binding lectins from dietary sources and SRL on proliferation and cell cycle progression in human colon HT29 and SW620 cells
Published in Nutrition and Cancer, 2019
Shivakumar Belur, Srikanth Barkeer, Bale M. Swamy, Lu-Gang Yu, Shashikala R. Inamdar
In the present study, all the five TF binding lectins differentially regulated cyclins involved in G1 to S transition phase. PNA, ACA, and JAC slightly reduced cyclin D1 expression whereas SRL and ABL totally diminished D1 expression which falls in line with our previous reports that SRL induces cellular apoptosis in HT 29 cells (16). Cyclin D2 expression was completely abolished by the presence of each of the lectins compared to control. Surprisingly all the five lectins have shown to reduce the expression of Cyclin D2 including PNA and ACA contradicting their proliferative response. Cyclin D3 expression was significantly reduced by SRL and moderately reduced by PNA and ACA. In contrast cyclin D3 levels were not affected either by ABL or JAC. Overexpression of cyclins D1, D2, and D3 has been reported in a large number of tumors. Overexpression of cyclins D1 and/or D2, but not cyclin D3, is reported to correlate with colon carcinogenesis (36). Inhibition of cyclin D1 expression has shown to inhibit growth and tumorigenicity of human colon cancer cells (37). Hence, down-regulation of cyclin D1 and D2 levels by SRL, ABL, and JAC consequently arrests the cells at G0/G1 phase. In contrast to cyclin D1 and D2, cyclin D3 has been shown to play positive role in colon epithelial cell differentiation but not in colon carcinogenesis (38). Proliferative lectins PNA and ACA may promote cell proliferation by decreasing cell cyclin D3 levels which is known to induce differentiation.
An evaluation of fulvestrant for the treatment of metastatic breast cancer
Published in Expert Opinion on Pharmacotherapy, 2019
Mohsin Soleja, Ganesh V. Raj, Nisha Unni
Multiple mechanisms of endocrine resistance have been explored. About 15–20% of tumors lose ER at time of progression [48,49]. Thus, a majority of hormone receptor positive tumors maintain ER expression with resistance through alternative mechanisms. In vitro models of fulvestrant-resistant breast cancer cell lines have shown heterogeneous ER independent transcriptional programs contributing to fulvestrant resistance. These include upregulation of cyclin D3, cyclin E2, CDK2, CDK4/6 causing alterations in cell cycle regulation [50].