Ribociclib, a selective cyclin D kinase 4/6 inhibitor, inhibits proliferation and induces apoptosis of human cervical cancer in vitro and in vivo

Xiong, Yudi; Li, Tianqi; Assani, Ganiou; Ling, Huan; Zhou, Qian; Zeng, Yongquan; Zhou, Fen; Zhou, Youwen

doi:10.1016/j.biopha.2019.108602

Cited by 44 publications

(27 citation statements)

References 34 publications

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“…The increasing apoptotic cells through flow cytometry analysis and the decreasing Bcl-2 level (anti-apoptotic protein) by western blotting had verified it. However, the pro-apoptotic protein Bax didn't express higher as we have observed in cervical cancer [13], but gradually lessened on the contrary. It may be persuasive that LEE011 induced more cell autophagy and senescence than apoptosis in MDA-MB-231 [30,40].…”

Section: Discussionmentioning

confidence: 47%

“…Owing to the following dysregulation in E2F downstream genes FoxM1, CCNA1, Myc [10], this impediment may facilitate G 1 -S cell cycle arrest and halts cell proliferation ultimately [29]. Additionally, different from what we have presumed [13,30], tiny changes occurred with P16, which could be explained as limited necessity of P16 (CDNK2A) for TNBC [31]. Disruptions upon the CDK4/6-cyclin D-P16-Rb pathway have emerged frequently in many human cancers [32,33], considering its highest negativity with TNBC group [34], we may find it not too hard to contact this two events together.…”

Section: Discussionmentioning

confidence: 72%

“…Amplification and overactivation of the CDK4/6-cyclin D-Rb-E2F pathway have been observed in various malignancies including breast cancer [10][11][12][13][14][15]. Considering that the dysfunctional CDKs can drive unscheduled cell cycle progression, inhibitors targeting the combination between CDKs with D-type cyclins might be an imposing strategy [16].…”

Section: Introductionmentioning

confidence: 99%

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Ribociclib (LEE011) suppresses cell proliferation and induces apoptosis of MDA-MB-231 by inhibiting CDK4/6-cyclin D-Rb-E2F pathway

Xiong

Wang

et al. 2019

Artificial Cells, Nanomedicine, and Biotechnology

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Triple-negative breast cancer (TNBC) stands for a refractory subtype, which predicts poor prognosis and has no effective therapies yet for improving it. Given the restrictions of traditional treatments, novel therapeutic strategies need excavating to alleviate the intrinsic or acquired resistance. Ribociclib, a selective CDK4/6 inhibitor, has successfully prevented cancers from deteriorating by intervening the CDK4/6-cyclin D-Rb-E2F pathway, especially for estrogen receptor-positive (ER þ) breast cancer. However, there still remains limited accessibility referring to TNBC. Performing experiments on MDA-MB-231 cells, we found that LEE011 could suppress cell proliferation, and this suppression tended to be dose-dependently. Western blotting analysis presented significant decrease with the expression of CDK4/6 after LEE011 treated, and other proteins associated with this axis such as cyclin D1, p-Rb, Rb, E2F1 showed aberrant changes. Moreover, LEE011 induced G 0-G 1 phase cell cycle arrest, promoted cell apoptosis, and reduced cell migration in vitro. In addition, tumor growth was remarkably impeded without obvious side-effects in MDA-MB-231 xenograft models. Our research has identified that LEE011 was not completely invalid for MDA-MB-231. Considering its pivotal status in TNBC, the CDK4/6-cyclin D-Rb-E2F pathway informed us the possibility and practicality of Ribociclib (LEE011) as pharmacological intervention, but challenges warrant further validation in prospective studies.

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Section: Discussionmentioning

confidence: 47%

Section: Discussionmentioning

confidence: 72%

Section: Introductionmentioning

confidence: 99%

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Ribociclib (LEE011) suppresses cell proliferation and induces apoptosis of MDA-MB-231 by inhibiting CDK4/6-cyclin D-Rb-E2F pathway

Xiong

Wang

et al. 2019

Artificial Cells, Nanomedicine, and Biotechnology

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“…When RB is phosphorylated, its growth-suppressive properties are inactivated, and then releasing the E2Fs. Ampli cation and overactivation of the CDK4/6-cyclin D-RB-E2F pathway have been observed in various malignancies including breast cancer [7][8][9][10][11][12]. Selective CDK4/6 inhibitors "turn off" these kinases and dephosphorylate RB, resulting in a block of cell-cycle progression in mid-G1 and preventing proliferation of cancer cells [13].…”

Section: Introductionmentioning

confidence: 99%

A Novel Sequential Treatment of Palbociclib Enhances the Effect of Cisplatin in RB-Proficient Triple-Negative Breast Cancer

Huang

Li³

2020

Preprint

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Background: Triple-negative breast cancer (TNBC) is a highly aggressive malignancy lack of sensitivity to chemo-, endocrine and targeted therapy. CDK4/6 inhibitors, combined with endocrine therapy, have been proven to be effective in postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer. So we investigated that whether CDK4/6 inhibitor palbociclib (PD) could enhance effects of cisplatin (CDDP) on TNBC.Methods: The effects of different drug regimens of PD and CDDP on MDA-MB-231 and RB-knockdown MDA-MB-231 (sh-MDA-MB-231) cells was assessed in vitro and vivo. Immunoblotting illustrated cyclin D1/RB/E2F axis signaling pathway.Results: PD induced G1 phase cell cycle arrest in MDA-MB-231 cell line. However, neither concomitant treatment with PD and CDDP nor immediately sequential treatment with CDDP before or after PD had an influence on cell apoptosis of MDA-MB-231 cells. We further investigated the effect of PD or CDDP withdrawal on the sequential treatment and found that PD used for 48h and then withdrawn for 48h followed by CDDP could significantly increase apoptosis, inhibit cell proliferation, cloning formation and mitotic progression of MDA-MB-231 cells, while in other regimens PD and CDDP represented additive or antagonistic response. PD preferential use synchronized tumor cell cycle which could increase DNA damage by CDDP as measured by γH2AX. These findings above were negative in sh-MDA-MB-231 cells, which indicated that PD enhances the sensitivity of TNBC cells to CDDP in a RB dependent manner. In vivo, this combination treatment inhibited tumor growth and Ki-67 expression compared with single drug treatments in MDA-MB-231 xenograft models. Western blotting analysis presented that PD enhanced sensitivity to CDDP through CDK4/6-cyclin D-RB-E2F pathway. Conclusions: This study indicates that the anti-tumor effect of PD-CDDP functions through CDK4/6-cyclin D1-RB-E2F pathway and the synchronization of cell cycle. PD-CDDP Our study provides a novel and potentially effective treatment for TNBC patients.

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“…Ampli cation and overactivation of the CDK4/6-cyclin D-RB-E2F pathway have been observed in various malignancies including breast cancer [7][8][9][10][11][12]. Selective CDK4/6 inhibitors "turn off" these kinases and dephosphorylate RB, resulting in a block of cell-cycle progression in mid-G1 and preventing proliferation of cancer cells [13].…”

mentioning

confidence: 99%

A novel sequential treatment of palbociclib enhances the effect of cisplatin in RB-proficient triple-negative breast cancer

Huang

2020

Preprint

View full text Add to dashboard Cite

Background: Triple-negative breast cancer (TNBC) is a highly aggressive malignancy lack of sensitivity to chemo-, endocrine and targeted therapy. CDK4/6 inhibitors, combined with endocrine therapy, have been proven to be effective in postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer. So we investigated that whether CDK4/6 inhibitor palbociclib (PD) could enhance effects of cisplatin (CDDP) on TNBC.Methods: The effects of different drug regimens of PD and CDDP on MDA-MB-231 and RB-knockdown MDA-MB-231 (sh-MDA-MB-231) cells were assessed in vitro and vivo. MDA-MB-468 and RB-overexpression MDA-MB-468 cells were used to assess the effect of PD-CDDP regimen in vitro. Immunoblotting illustrated cyclin D1/RB/E2F axis signaling pathway.Results: PD induced G1 phase cell cycle arrest in MDA-MB-231 cell line. However, synchronous treatment with PD and CDDP for 24h, PD used for 24h and then followed by CDDP or CDDP used for 24h and then followed by PD all had no influence on cell apoptosis of MDA-MB-231 cells. We further investigated the effect of PD or CDDP withdrawal on sequential treatment and found that PD used for 48h and then withdrawn for 48h followed by CDDP (PD-CDDP) could significantly increase apoptosis, inhibit cell viability and colony formation of MDA-MB-231 cells, while in other regimens PD and CDDP represented additive or antagonistic response. Preferential use of PD could increase DNA damage by CDDP as measured through γH2AX. These findings above were negative in sh-MDA-MB-231 cells and cell function experiments of MDA-MB-468 and RB-overexpression MDA-MB-468 cells could draw similar conclusions, which indicated that PD enhanced the sensitivity of TNBC cells to CDDP in a RB dependent manner. In vivo, this combination treatment inhibited tumor growth and Ki-67 expression compared with single drug treatments in MDA-MB-231 xenograft models. Western blotting analysis presented that PD enhanced sensitivity to CDDP through CDK4/6-cyclin D-RB-E2F pathway. Conclusions: Pre-treatment with PD synchronized tumor cell cycle through CDK4/6-cyclin D1-RB-E2F pathway, which could increase anti-tumor effect of CDDP. PD-CDDP might be an effective treatment for RB-proficient TNBC patients.

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Ribociclib, a selective cyclin D kinase 4/6 inhibitor, inhibits proliferation and induces apoptosis of human cervical cancer in vitro and in vivo

Cited by 44 publications

References 34 publications

Ribociclib (LEE011) suppresses cell proliferation and induces apoptosis of MDA-MB-231 by inhibiting CDK4/6-cyclin D-Rb-E2F pathway

Ribociclib (LEE011) suppresses cell proliferation and induces apoptosis of MDA-MB-231 by inhibiting CDK4/6-cyclin D-Rb-E2F pathway

A Novel Sequential Treatment of Palbociclib Enhances the Effect of Cisplatin in RB-Proficient Triple-Negative Breast Cancer

A novel sequential treatment of palbociclib enhances the effect of cisplatin in RB-proficient triple-negative breast cancer

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