The p21 levels have the potential to be a monitoring marker for ribociclib in breast cancer

Iida, Masafumi; Nakamura, Misato; Tokuda, Emi; Toyosawa, Daichi; Niwa, Toshifumi; Ohuchi, Noriaki; Ishida, Toru; Hayashi, Shin Ichi

doi:10.18632/oncotarget.27127

Cited by 22 publications

(15 citation statements)

References 34 publications

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“…The released E 2 F transcription factors are then free to activate genes required for entry into the S phase and DNA replication [ 29 ]. In addition, a recent study reported that p21 levels were proportional to CDK4/6 inhibitor sensitivity and had the potential as a monitoring marker for ribociclib, an FDA-approved CDK4/6 inhibitor in late-stage breast cancer [ 30 ]. Notably, while our combination L30I40 significantly decreased CDK4/6 protein levels, we found that LUT targeted CDK4 only, but I3C preferred CDK6 exclusively, indicating that the synergistic inhibition of CD4/6 complex results from the combination of the inhibition of CDK4 by LUT and the suppression of CDK6 by I3C.…”

Section: Discussionmentioning

confidence: 99%

Combined Luteolin and Indole-3-Carbinol Synergistically Constrains ERα-Positive Breast Cancer by Dual Inhibiting Estrogen Receptor Alpha and Cyclin-Dependent Kinase 4/6 Pathway in Cultured Cells and Xenograft Mice

Wang

Zhang

Dai

et al. 2021

Cancers

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The high concentrations of individual phytochemicals in vitro studies cannot be physiologically achieved in humans. Our solution for this concentration gap between in vitro and human studies is to combine two or more phytochemicals. We screened 12 phytochemicals by pairwise combining two compounds at a low level to select combinations exerting the synergistic inhibitory effect of breast cancer cell proliferation. A novel combination of luteolin at 30 μM (LUT30) and indole-3-carbinol 40 μM (I3C40) identified that this combination (L30I40) synergistically constrains ERα+ breast cancer cell (MCF7 and T47D) proliferation only, but not triple-negative breast cancer cells. At the same time, the individual LUT30 and I3C40 do not have this anti-proliferative effect in ERα+ breast cancer cells. Moreover, this combination L30I40 does not have toxicity on endothelial cells compared to the current commercial drugs. Similarly, the combination of LUT and I3C (LUT10 mg + I3C10 mg/kg/day) (IP injection) synergistically suppresses tumor growth in MCF7 cells-derived xenograft mice, but the individual LUT (10 mg/kg/day) and I3C (20 mg/kg/day) do not show an inhibitory effect. This combination synergistically downregulates two major therapeutic targets ERα and cyclin dependent kinase (CDK) 4/6/retinoblastoma (Rb) pathway, both in cultured cells and xenograft tumors. These results provide a solid foundation that a combination of LUT and I3C may be a practical approach to treat ERα+ breast cancer cells after clinical trials.

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Section: Discussionmentioning

confidence: 99%

Combined Luteolin and Indole-3-Carbinol Synergistically Constrains ERα-Positive Breast Cancer by Dual Inhibiting Estrogen Receptor Alpha and Cyclin-Dependent Kinase 4/6 Pathway in Cultured Cells and Xenograft Mice

Wang

Zhang

Dai

et al. 2021

Cancers

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“…Other pathways that converge on CDK2 activation are changes to the CDK inhibitor proteins p21 Cip1/Waf1 and p27 Kip1 . This includes reduction of p21 Cip1/Waf1 (Iida et al 2019) and p27 Kip1 protein (Dean et al 2010). Increased expression of components of the cyclin D-CDK4/6 complexes such as CDK6, observed in (Yang et al 2017) and (Cornell et al 2019), could also increase CDK2 activity by engaging the p21 Cip1/Waf1 and p27 Kip1 inhibitory proteins and hence remove these inhibitors from CDK2 complexes (Tsubari et al 1999).…”

Section: :5mentioning

confidence: 99%

Cyclin E1 and cyclin E2 in ER+ breast cancer: prospects as biomarkers and therapeutic targets

Milioli

Alexandrou

Lim

et al. 2020

Endocrine-Related Cancer

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Cyclin E1 is one the most promising biomarkers in estrogen receptor positive (ER+) breast cancer for response to the new standard of care drug class, CDK4/6 inhibitors. Because of its strong predictive value, cyclin E1 expression may be used in the future to triage patients into potential responders and non-responders. Importantly, cyclin E1 is highly related to cyclin E2, and both cyclin E1 and cyclin E2 are estrogen target genes that can facilitate anti-estrogen resistance and can be highly expressed in breast cancer. However cyclin E1 and E2 are often expressed in different subsets of patients. This raises questions about whether the expression of cyclin E1 and cyclin E2 have different biological drivers, if high expressing subsets represent different clinical subtypes, and how to effectively develop a biomarker for E-cyclin expression. Finally, several pan-CDK inhibitors that target cyclin E-CDK2 activity have reached Phase II clinical trials. In this review, we outline the data identifying that different cohorts of patients have high expression of cyclins E1 and E2 in ER+ cancer and address the implications for biomarker and therapeutic development.

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“…Based on the IC 50 s of PAL or ABE, the PAL-or ABE-resistant MCF-7 or KPL-1 cells were 3 to 6 times more cross-resistant to APL and ABE, respectively (Table 1). Cross-resistance among CDK4/6 inhibitors has been reported in both preclinical and clinical conditions [1,[10][11][12].…”

Section: Discussionmentioning

confidence: 99%

Resistance to cyclin-dependent kinase (CDK) 4/6 inhibitors confers cross-resistance to other CDK inhibitors but not to chemotherapeutic agents in breast cancer cells

et al. 2020

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Background Combined endocrine therapy with a cyclin-dependent kinase (CDK) 4/6 inhibitor has been indicated to improve not only progression-free survival, but also overall survival in patients with hormone receptor (HR)-positive, HER2-negative advanced breast cancer. However, resistance to this combination therapy inevitably develops. How to manage this resistant breast cancer is one of the most important clinical issues. To investigate the mechanisms of action responsible for resistance, we developed breast cancer cells resistant to CDK4/6 inhibitors, and analyzed their biological characteristics and sensitivity to different anticancer agents. Methods HR-positive, HER2-negative MCF-7 and KPL-1 breast cancer cells were cultivated in palbociclib (PAL) or abemaciclib (ABE)-added culture medium for over 5 months, and we successfully developed PAL-or ABE-resistant cells. The effects of PAL or ABE on the cell growth, basal RB expression, RB phosphorylation, cell cycle and cell senescence were compared between resistant and parental cells. Effects of the other CDK4/6 inhibitor, different chemotherapeutic agents and estrogen on the cell growth were also examined. The expression levels of cyclin D1, CDK2, CDK4, CDK6, cyclin E1 and estrogen receptor (ER)-ɑ were measured using RT-PCR. Results Long-term exposure to up to 200 nM PAL or ABE resulted in the development of PAL-or ABE-resistant MCF-7 or KPL-1 breast cancer cells. Basal expression levels of RB in both resistant cells were down-regulated. Inhibitory effects of either PAL or ABE on RB phosphorylation were reduced in both resistant cells. Accordingly, G1-S cell cycle retardation and cell senescence induced by either inhibitor were also attenuated in both resistant cells. Both resistant cells were crossresistant to the other CDK4/6 inhibitor but almost as equally sensitive to different chemotherapeutic agents (5-fluorouracil, gemcitabine, paclitaxel, docetaxel, doxorubicin and eribulin) as the parental cells. The mRNA expression level of CDK6 significantly increased in the resistant MCF-7 cells and that of Rb1 significantly decreased in the resistant KPL-1 cells. Although both resistant cells were less sensitive to estrogen than the parental cells, the expression levels of ER-ɑ did not significantly change in either. Conclusions Our study suggests that acquired resistance to PAL or ABE confers cross-resistance to the other CDK4/6 inhibitor but not to chemotherapeutic agents in HR-positive, HER2-negative breast cancer cells. Down-regulation of basal RB expression and normalized RB phosphorylation reduced by CDK4/6 inhibitors may be responsible for the attenuated anti-cell growth effects of the inhibitors.

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The p21 levels have the potential to be a monitoring marker for ribociclib in breast cancer

Cited by 22 publications

References 34 publications

Combined Luteolin and Indole-3-Carbinol Synergistically Constrains ERα-Positive Breast Cancer by Dual Inhibiting Estrogen Receptor Alpha and Cyclin-Dependent Kinase 4/6 Pathway in Cultured Cells and Xenograft Mice

Combined Luteolin and Indole-3-Carbinol Synergistically Constrains ERα-Positive Breast Cancer by Dual Inhibiting Estrogen Receptor Alpha and Cyclin-Dependent Kinase 4/6 Pathway in Cultured Cells and Xenograft Mice

Cyclin E1 and cyclin E2 in ER+ breast cancer: prospects as biomarkers and therapeutic targets

Resistance to cyclin-dependent kinase (CDK) 4/6 inhibitors confers cross-resistance to other CDK inhibitors but not to chemotherapeutic agents in breast cancer cells

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