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  1. Fulltext Final Results of RIGHT Choice: Ribociclib Plus Endocrine Therapy Versus Combination Chemotherapy in Premenopausal Women With Clinically Aggressive Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer
    Lu YS, Mahidin EIBM, Azim H, Eralp Y, Yap YS, Im SA, et al.
    J Clin Oncol, 2024 Aug 10;42(23):2812-2821.
    PMID: 38771995 DOI: 10.1200/JCO.24.00144
    PURPOSE: A head-to-head comparison of efficacy between a cyclin-dependent kinase 4/6 inhibitor plus endocrine therapy (ET) versus combination chemotherapy (CT) has never been reported in patients with clinically aggressive hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC).

    METHODS: In this open-label, multicenter, randomized phase II trial, pre/perimenopausal women with clinically aggressive HR+/HER2- ABC were randomly assigned 1:1 to first-line ribociclib (600 mg once daily; 3 weeks on, 1 week off) plus letrozole/anastrozole and goserelin or investigator's choice of combination CT (docetaxel plus capecitabine, paclitaxel plus gemcitabine, or capecitabine plus vinorelbine). The primary end point was progression-free survival (PFS).

    RESULTS: Among 222 patients randomly assigned to ribociclib plus ET (n = 112) or combination CT (n = 110), 150 (67.6%) had symptomatic visceral metastases, 41 (18.5%) had rapid disease progression per investigator's judgment, and 31 (14.0%) had symptomatic nonvisceral disease. Overall, 106 (47.7%) patients had investigator-assessed visceral crisis. The median follow-up time was 37.0 months. At data cutoff, 31.3% (ribociclib arm) and 15.5% (CT arm) of patients had completed study treatment and transitioned to post-trial access. The median PFS was 21.8 months (ribociclib plus ET; [95% CI, 17.4 to 26.7]) and 12.8 months (combination CT; [95% CI, 10.1 to 18.4); hazard ratio, 0.61 [95% CI, 0.43 to 0.87]; P = .003. The overall response rates and the median time to response in the ribociclib versus CT arms, respectively, were 66.1% and 61.8% and 4.9 months and 3.2 months (hazard ratio, 0.76 [95% CI, 0.55 to 1.06]). Lower rates of symptomatic adverse events were observed in the ribociclib versus CT arm.

    CONCLUSION: First-line ribociclib plus ET showed a significant PFS benefit, similar response rates, and better tolerability over combination CT in patients with clinically aggressive HR+/HER2- ABC.

    Matched MeSH terms: Cyclin-Dependent Kinase 4/antagonists & inhibitors
  2. Fulltext Expression of senescence-associated microRNAs and target genes in cellular aging and modulation by tocotrienol-rich fraction
    Khee SG, Yusof YA, Makpol S
    Oxid Med Cell Longev, 2014;2014:725929.
    PMID: 25132913 DOI: 10.1155/2014/725929
    Emerging evidences highlight the implication of microRNAs as a posttranscriptional regulator in aging. Several senescence-associated microRNAs (SA-miRNAs) are found to be differentially expressed during cellular senescence. However, the role of dietary compounds on SA-miRNAs remains elusive. This study aimed to elucidate the modulatory role of tocotrienol-rich fraction (TRF) on SA-miRNAs (miR-20a, miR-24, miR-34a, miR-106a, and miR-449a) and established target genes of miR-34a (CCND1, CDK4, and SIRT1) during replicative senescence of human diploid fibroblasts (HDFs). Primary cultures of HDFs at young and senescent were incubated with TRF at 0.5 mg/mL. Taqman microRNA assay showed significant upregulation of miR-24 and miR-34a and downregulation of miR-20a and miR-449a in senescent HDFs (P < 0.05). TRF reduced miR-34a expression in senescent HDFs and increased miR-20a expression in young HDFs and increased miR-449a expression in both young and senescent HDFs. Our results also demonstrated that ectopic expression of miR-34a reduced the expression of CDK4 significantly (P < 0.05). TRF inhibited miR-34a expression thus relieved its inhibition on CDK4 gene expression. No significant change was observed on the expression of CCND1, SIRT1, and miR-34a upstream transcriptional regulator, TP53. In conclusion tocotrienol-rich fraction prevented cellular senescence of human diploid fibroblasts via modulation of SA-miRNAs and target genes expression.
    Matched MeSH terms: Cyclin-Dependent Kinase 4/genetics; Cyclin-Dependent Kinase 4/metabolism
  3. SRJ09, a promising anticancer drug lead: Elucidation of mechanisms of antiproliferative and apoptogenic effects and assessment of in vivo antitumor efficacy
    Wong CC, Lim SH, Sagineedu SR, Lajis NH, Stanslas J
    Pharmacol Res, 2016 05;107:66-78.
    PMID: 26940565 DOI: 10.1016/j.phrs.2016.02.024
    SRJ09 (3,19-(2-bromobenzylidene)andrographolide), a semisynthetic andrographolide (AGP) derivative, was shown to induce G1 cell cycle arrest and eventually apoptosis in breast and colon cancer cell lines. The present investigation was carried out to elucidate the mechanisms cell cycle arrest and apoptosis and evaluate the in vivo antitumor activity of SRJ09. The in vitro growth inhibitory properties of compounds were assessed in colon (HCT-116) and breast (MCF-7) cancer cell lines. Immunoblotting was utilized to quantitate the protein levels in cells. The gene expressions were determined using reverse transcriptase PCR (RT-PCR). Pharmacokinetic investigation was carried out by determining SRJ09 levels in plasma of Balb/C mice using HPLC. In vivo antitumor activity was evaluated in athymic mice carrying HCT-116 colon tumor xenografts. SRJ09 displayed improved in vitro activity when compared with AGP by producing rapid cell killing effect in vitro. Its activity was not compromised in MES-SA/Dx5 multidrug resistant (MDR) cells expressing p-glycoprotein. Cells treated with SRJ09 (0.1-10μM) displayed increased p21 protein level, which corresponded with gene expression. Whereas CDK4 protein level and gene expression was suppressed. The treatment did not affect cyclin D1. Changes of these proteins paralleled G1 cell cycle arrest in both cell lines as determined by flow cytometry. Induction of apoptosis by SRJ09 in HCT-116 cells which occurred independent of p53 and bcl-2 was inhibited in the presence of caspase 8 inhibitor, implicating the extrinsic apoptotic pathway. A single dose (100mg/kg, i.p) of SRJ09 produced a plasma concentration range of 12-30.4μM. At 400mg/kg (q4dX3), it significantly retarded growth of tumor xenografts. The antitumor activity of SRJ09 is suggested mediated via the induction of p21 expression and suppression of CDK-4 expression without affecting cyclin D1 to trigger G1 arrest leading to apoptosis.
    Matched MeSH terms: Cyclin-Dependent Kinase 4/genetics; Cyclin-Dependent Kinase 4/metabolism
  4. Fulltext Inhibitors targeting CDK4/6, PARP and PI3K in breast cancer: a review
    Nur Husna SM, Tan HT, Mohamud R, Dyhl-Polk A, Wong KK
    Ther Adv Med Oncol, 2018;10:1758835918808509.
    PMID: 30542378 DOI: 10.1177/1758835918808509
    Breast cancer is the global leading cause of cancer-related death in women and it represents a major health burden worldwide. One of the promising breast cancer therapeutic avenues is through small molecule inhibitors (SMIs) which have undergone rapid progress with successful clinical trials. Recently, three emerging and vital groups of proteins are targeted by SMIs for breast cancer treatment, namely cyclin-dependent kinase 4 and 6 (CDK4/6), poly (adenosine diphosphate-ribose) polymerase (PARP) and phosphoinositide 3-kinase (PI3K). Several of these inhibitors have been approved for the treatment of breast cancer patients or progressed into late-stage clinical trials. Thus, modeling from these successful clinical trials, as well as their limitations, is pivotal for future development and trials of other inhibitors or therapeutic regimens targeting breast cancer patients. In this review, we discuss eight recently approved or novel SMIs against CDK4/6 (palbociclib, ribociclib and abemaciclib), PARP (olaparib, veliparib and talazoparib), and PI3K (buparlisib and alpelisib). The mechanisms of action, series of clinical trials and limitations are described for each inhibitor.
    Matched MeSH terms: Cyclin-Dependent Kinase 4
  5. HPV infection and the alterations of the pRB pathway in oral carcinogenesis
    Lim KP, Hamid S, Lau SH, Teo SH, Cheong SC
    Oncol Rep, 2007 Jun;17(6):1321-6.
    PMID: 17487385 DOI: 10.3892/or.17.6.1321
    Inactivation of the retinoblastoma (pRB) pathway is a common event in oral squamous cell carcinoma particularly through the aberrant expression of the components within this pathway. This study examines the alterations of molecules within the pRB pathway by looking at the presence of homozygous deletions in p16(INK4A) and the expression patterns of pRB, cyclin D1 and CDK4, as well as the presence of human papillomavirus (HPV) in our samples. In our study, 5/20 samples demonstrated deletions of p16(INK4A) exon 1alpha. pRB overexpression was found in 20/20 samples, the expression was mainly observed in all layers of the epithelia, particularly in the basal layer where cells are actively dividing and aberrant pRB expression was found in 12/20 samples. Cyclin D1 and CDK4 overexpression was detected in 6/20 and 2/20 samples respectively in comparison to hyperplasias where both proteins were either not expressed or expressed at minimal levels (<10%). Strikingly, HPV was found to be present in all of our samples, suggesting that HPV plays a significant role in driving oral carcinogenesis. Notably, 17/20 of our samples showed more than one alteration in the pRB pathway, however, we did not find any significant relationship between the presence of HPV, homozygous deletion of p16(INK4A) and overexpression of pRB, cyclin D1 and CDK4. Collectively, this data demonstrates that alterations in the pRB pathway are a common event and involve the aberration of more than one molecule within the pathway. Furthermore, the involvement of HPV in all our samples suggests that HPV infection may play an important role in oral carcinogenesis.
    Matched MeSH terms: Cyclin-Dependent Kinase 4/analysis; Cyclin-Dependent Kinase 4/metabolism
  6. iTRAQ-based proteomic identification of proteins involved in anti-angiogenic effects of Panduratin A on HUVECs
    Lai SL, Wong PF, Lim TK, Lin Q, Mustafa MR
    Phytomedicine, 2015 Jan 15;22(1):203-12.
    PMID: 25636890 DOI: 10.1016/j.phymed.2014.11.016
    Panduratin A (PA), a cyclohexanyl chalcone from Boesenbergia rotunda (L.) Mansf. was shown to possess anti-angiogenic effects in our previous study. In the present study, the molecular targets and anti-angiogenic mechanisms of PA on human umbilical vein endothelial cells (HUVECs) were identified using an iTRAQ-based quantitative proteomics approach. A total of 263 proteins were found to be differentially regulated in response to treatment with PA. Ingenuity Pathway Analysis revealed that cellular growth and proliferation, protein synthesis, RNA post-transcriptional modification, cellular assembly and organization and cell-to-cell signaling and interaction were the most significantly deregulated molecular and cellular functions in PA-treated HUVECs. PA inhibited the expressions of ARPC2 and CTNND1 that are associated with the formation of actin cytoskeleton, focal adhesion and cellular protrusions. In addition, PA down-regulated CD63, GRB-2, ICAM-2 and STAB-1 that are implicated in adhesion, migration and tube formation of endothelial cells. The differential expressions of three targets, namely, ARPC2, CDK4, and GRB-2 were validated by western blot analyses. Furthermore, PA inhibited G1-S progression, and resulted in G0/G1 arrest in HUVECs. The blockage in cell cycle progression was accompanied with the suppression of mTOR signaling. Treatment of HUVECs with PA resulted in decreased phosphorylation of ribosomal S6 and 4EBP1 proteins, the two downstream effectors of mTOR signaling. We further showed that PA is able to inhibit mTOR signaling induced by VEGF, a potent inducer of angiogenesis. Taken together, by integrating quantitative proteomic approach, we identified protein targets in which PA mediates its anti-angiogenic effects. The present study thus provides mechanistic evidence to the previously reported multifaceted anti-angiogenic effects of PA. Our study further identified mTOR signaling as an important target of PA, and therefore highlights the potential of PA for therapeutic intervention against angiogenesis-related pathogenesis, particularly, metastatic malignancy.
    Matched MeSH terms: Cyclin-Dependent Kinase 4/metabolism
  7. Palbociclib and beyond for the treatment of HR + HER2- metastatic breast cancer: an Asian-Pacific perspective and practical management guide on the use of CDK4/6 inhibitors
    Dawood S, Chiu JW, Huang CS, Nag S, Sookprasert A, Yap YS, et al.
    Curr Med Res Opin, 2020 08;36(8):1363-1373.
    PMID: 32544344 DOI: 10.1080/03007995.2020.1783646
    Breast cancer is the most frequent cancer amongst women worldwide including in Asia where the incidence rate is rapidly increasing. Even with treatment, around 30% of patients with early breast cancer progress to metastatic disease, with hormone receptor positive (HR+) and human epidermal growth factor receptor 2 negative (HER2-) breast cancer the most common phenotype. First-line endocrine therapy targeting the estrogen receptor signaling pathway provides a median progression-free survival or time to progression of 6-15 months in HR + HER2- metastatic breast cancer. Recently, cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, combined with endocrine therapy, have achieved more than two years median progression-free survival in HR + HER2- metastatic breast cancer. However, the characteristics of the Asian breast cancer population differ from those of Western populations and need to be considered when selecting a suitable treatment. Breast cancer is diagnosed at a younger age in Asian populations and late stage at presentation is generally more common in low-/middle-income countries than high-income countries. Consequently, the proportion of premenopausal women with metastatic breast cancer is higher in Asian compared with Western populations. While CDK4/6 inhibitors have been approved in the USA (FDA) since 2015, experience with them in Asia is more limited. We review the experience with the CDK4/6 inhibitor palbociclib in Asian patients with HR + HER2- metastatic breast cancer and provide guidance on the use of palbociclib in these patients.
    Matched MeSH terms: Cyclin-Dependent Kinase 4/antagonists & inhibitors*
  8. Fulltext An Intrinsic Mitochondrial Pathway Is Required for Phytic Acid-Chitosan-Iron Oxide Nanocomposite (Phy-CS-MNP) to Induce G₀/G₁ Cell Cycle Arrest and Apoptosis in the Human Colorectal Cancer (HT-29) Cell Line
    Tan BL, Norhaizan ME, Chan LC
    Pharmaceutics, 2018 Oct 23;10(4).
    PMID: 30360519 DOI: 10.3390/pharmaceutics10040198
    Magnetic iron oxide nanoparticles are among the most useful metal nanoparticles in biomedical applications. A previous study had confirmed that phytic acid-chitosan-iron oxide nanocomposite (Phy-CS-MNP) exhibited antiproliferative activity towards human colorectal cancer (HT-29) cells. Hence, in this work, we explored the in vitro cytotoxicity activity and mechanistic action of Phy-CS-MNP nanocomposite in modulating gene and protein expression profiles in HT-29 cell lines. Cell cycle arrest and apoptosis were evaluated by NovoCyte Flow Cytometer. The mRNA changes (cyclin-dependent kinase 4 (Cdk4), vascular endothelial growth factor A (VEGFA), c-Jun N-terminal kinase 1 (JNK1), inducible nitric oxide synthase (iNOS), and matrix metallopeptidase 9 (MMP9)) and protein expression (nuclear factor-kappa B (NF-κB) and cytochrome c) were assessed by quantitative real-time polymerase chain reaction (PCR) and western blotting, respectively. The data from our study demonstrated that treatment with Phy-CS-MNP nanocomposite triggered apoptosis and G₀/G₁ cell cycle arrest. The transcriptional activity of JNK1 and iNOS was upregulated after treatment with 90 μg/mL Phy-CS-MNP nanocomposite. Our results suggested that Phy-CS-MNP nanocomposite induced apoptosis and cell cycle arrest via an intrinsic mitochondrial pathway through modulation of Bax and Bcl-2 and the release of cytochrome c from the mitochondria into the cytosol.
    Matched MeSH terms: Cyclin-Dependent Kinase 4
  9. Fulltext IFITM3 knockdown reduces the expression of CCND1 and CDK4 and suppresses the growth of oral squamous cell carcinoma cells
    Gan CP, Sam KK, Yee PS, Zainal NS, Lee BKB, Abdul Rahman ZA, et al.
    Cell Oncol (Dordr), 2019 Aug;42(4):477-490.
    PMID: 30949979 DOI: 10.1007/s13402-019-00437-z
    PURPOSE: Oral squamous cell carcinoma (OSCC) is a challenging disease to treat. Up to 50% of OSCC patients with advanced disease develop recurrences. Elucidation of key molecular mechanisms underlying OSCC development may provide opportunities to target specific genes and, thus, to improve patient survival. In this study, we examined the expression and functional role of interferon transmembrane protein 3 (IFITM3) in OSCC development.

    METHODS: The expression of IFITM3 in OSCC and normal oral mucosal tissues was assessed by qRT-PCR and immunohistochemistry. The role of IFITM3 in driving OSCC cell proliferation and survival was examined using siRNA-mediated gene knockdown, and the role of IFITM3 in driving cell cycle regulators was examined using Western blotting.

    RESULTS: We found that IFITM3 is overexpressed in more than 79% of primary OSCCs. We also found that IFITM3 knockdown led to impaired OSCC cell growth through inhibition of cell proliferation, induction of cell cycle arrest, senescence and apoptosis. In addition, we found that IFITM3 knockdown led to reduced expressions of CCND1 and CDK4 and reduced RB phosphorylation, leading to inhibition of OSCC cell growth. This information may be instrumental for the design of novel targeted therapeutic strategies.

    CONCLUSIONS: From our data we conclude that IFITM3 is overexpressed in OSCC and may regulate the CCND1-CDK4/6-pRB axis to mediate OSCC cell growth.

    Matched MeSH terms: Cyclin-Dependent Kinase 4/metabolism*
  10. Fulltext Benzylidene derivatives of andrographolide inhibit growth of breast and colon cancer cells in vitro by inducing G(1) arrest and apoptosis
    Jada SR, Matthews C, Saad MS, Hamzah AS, Lajis NH, Stevens MF, et al.
    Br J Pharmacol, 2008 Nov;155(5):641-54.
    PMID: 18806812 DOI: 10.1038/bjp.2008.368
    BACKGROUND AND PURPOSE: Andrographolide, the major phytoconstituent of Andrographis paniculata, was previously shown by us to have activity against breast cancer. This led to synthesis of new andrographolide analogues to find compounds with better activity than the parent compound. Selected benzylidene derivatives were investigated for their mechanisms of action by studying their effects on the cell cycle progression and cell death.
    EXPERIMENTAL APPROACH: Microculture tetrazolium, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and sulphorhodamine B (SRB) assays were utilized in assessing the in vitro growth inhibition and cytotoxicity of compounds. Flow cytometry was used to analyse the cell cycle distribution of control and treated cells. CDK1 and CDK4 levels were determined by western blotting. Apoptotic cell death was assessed by fluorescence microscopy and flow cytometry.
    KEY RESULTS: Compounds, in nanomolar to micromolar concentrations, exhibited growth inhibition and cytotoxicity in MCF-7 (breast) and HCT-116 (colon) cancer cells. In the NCI screen, 3,19-(2-bromobenzylidene) andrographolide (SRJ09) and 3,19-(3-chloro-4-fluorobenzylidene) andrographolide (SRJ23) showed greater cytotoxic potency and selectivity than andrographolide. SRJ09 and SRJ23 induced G(1) arrest and apoptosis in MCF-7 and HCT-116 cells, respectively. SRJ09 downregulated CDK4 but not CDK1 level in MCF-7 cells. Apoptosis induced by SRJ09 and SRJ23 in HCT-116 cells was confirmed by annexin V-FITC/PI flow cytometry analysis.
    CONCLUSION AND IMPLICATIONS: The new benzylidene derivatives of andrographolide are potential anticancer agents. SRJ09 emerged as the lead compound in this study, exhibiting anticancer activity by downregulating CDK4 to promote a G(1) phase cell cycle arrest, coupled with induction of apoptosis.
    Matched MeSH terms: Cyclin-Dependent Kinase 4/biosynthesis
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