Palbociclib induces activation of <scp>AMPK</scp> and inhibits hepatocellular carcinoma in a <scp>CDK</scp>4/6‐independent manner

Hsieh, Feng Shu; Chen, Yao Li; Hung, Ming-Hui; Chu, Pei Yi; Tsai, M. H.; Chen, Li Ju; Hsiao, Yung Jen; Shih, Chih Ting; Chang, Mao Ju; Chao, Tzu I.; Shiau, Chung Wai; Chen, Kuen Feng

doi:10.1002/1878-0261.12072

Cited by 61 publications

(54 citation statements)

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“…It was reported that CDK4/6 inhibitors induce autophagy 29‐35 . Based on the results described above, we speculated that the prominent vacuole formation in response to abemaciclib might be related to autophagy.…”

Section: Resultsmentioning

confidence: 53%

“…This observation also supports the idea that a target or targets other than CDK4/6 contribute to lysosomal dysfunction. Several previous studies reported induction of autophagy in response to CDK4/6 inhibitors 29‐34,50 . In this study, we sequentially monitored autophagic flux using fluorescence probe 37 ; this analysis revealed that all 3 CDK4/6 inhibitors tested inhibited autophagic flux at early time points.…”

Section: Discussionmentioning

confidence: 81%

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Abemaciclib induces atypical cell death in cancer cells characterized by formation of cytoplasmic vacuoles derived from lysosomes

et al. 2020

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In the cell cycle, the G1/S transition is controlled by the cyclin‐dependent kinase (CDK) 4/6‐cyclin D complex. Constitutive activation of CDK4/6 dysregulates G1/S transition, leading to oncogenic transformation. We found that 3 CDK4/6 inhibitors, abemaciclib, ribociclib, and palbociclib, exerted a cytocidal effect as well as a cytostatic effect at the G1 phase in cancer cell lines, including A549 human non–small cell lung cancer cells. Among these inhibitors, abemaciclib exhibited the most potent cytotoxic effect. The cell‐death phenotype induced by abemaciclib, which entailed formation of multiple cytoplasmic vacuoles, was not consistent with apoptosis or necroptosis. Abemaciclib blocked autophagic flux, resulting in accumulation of autophagosomes, however vacuole formation and cell death induced by abemaciclib were independent of autophagy. In addition, methuosis, a cell‐death phenotype characterized by vacuole formation induced by excessive macropinocytosis, was excluded because the vacuoles did not incorporate fluorescent dextran. Of note, both formation of vacuoles and induction of cell death in response to abemaciclib were inhibited by vacuolar‐type ATPase (V‐ATPase) inhibitors such as bafilomycin A1 and concanamycin A. Live‐cell imaging revealed that the abemaciclib‐induced vacuoles were derived from lysosomes that expanded following acidification. Transmission electron microscopy revealed that these vacuoles contained undigested debris and remnants of organelles. Cycloheximide chase assay revealed that lysosomal turnover was blocked by abemaciclib. Furthermore, mTORC1 inhibition along with partial lysosomal membrane permeabilization occurred after abemaciclib treatment. Together, these results indicate that, in cancer cells, abemaciclib induces a unique form of cell death accompanied by swollen and dysfunctional lysosomes.

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Section: Resultsmentioning

confidence: 53%

Section: Discussionmentioning

confidence: 81%

Abemaciclib induces atypical cell death in cancer cells characterized by formation of cytoplasmic vacuoles derived from lysosomes

et al. 2020

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“…All these suggest that autophagy is associated with the cell death induced in cells treated with palbociclib alone or in combination with SAHA. A previous study showed that palbociclib induced autophagy in hepatocellular carcinoma cells in a CDK4/6 independent manner, but through a mechanism involving 5′ AMP-activated protein kinase (AMPK) activation and protein phosphatase 5 (PP5) inhibition (62). Some earlier studies reported HDAC inhibitors could induce caspase-independent autophagic cell death in HeLa and chondrosarcoma (63,64).…”

Section: Palbociclib-resistant Npc Cells Were Sensitive To Cisplatinmentioning

confidence: 99%

Therapeutic Evaluation of Palbociclib and Its Compatibility with Other Chemotherapies in Primary and Recurrent Nasopharyngeal Carcinoma

Xue

Lui

et al. 2020

Preprint

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Background: Recent genomic analyses revealed that druggable molecule targets could only be detected in around 6% of nasopharyngeal carcinoma (NPC) patients. Yet, an addiction to dysregulated CDK4/6-cyclinD1 signalling pathway is an essential event in the pathogenesis of NPC. Using our newly established xenografts and cell lines derived from primary, recurrent and metastatic NPC, we aimed to evaluate the therapeutic efficacy of a specific CDK4/6 inhibitor, palbociclib, and its compatibility with other chemodrugs in treating NPC.Methods: The efficacy of single treatment of palbociclib on NPC models was first evaluated, followed by concurrent treatment with cisplatin or suberanilohydroxamic acid (SAHA). RNA sequencing was used to profile the related pathways in governing the drug response. Palbociclib-resistant NPC cell lines were also established to demonstrate if cisplatin could be used as a second-line treatment once the cells developed resistance to palbociclib. The efficacy of palbociclib treatment on cisplatin-resistant NPC cells was also examined. Results: Palbociclib single drug treatment was confirmed to have a cell cycle arresting effect of NPC cells in G1 phase in vitro. It also had a significant inhibitory effect in all the 6 NPC tumor models in vivo, with a substantial reduction in total tumor volume and proliferation marker Ki-67. Concurrent use of palbociclib dampened the cytotoxic effect of cisplatin in NPC cells in vitro. Notably, combination of palbociclib with SAHA resulted in synergistic cell death of NPC both in vitro and in vivo. Autophagy-associated cell death was found to be involved in the enhanced tumor growth inhibitory effect in the combined palbociclib+SAHA treatment. NPC cell lines trained to sustain growth in high dose of palbociclib and cisplatin remained sensitive in subsequent treatment of cisplatin or palbociclib respectively.Conclusions: This study provides essential evidences to position palbociclib as an alternative therapeutic option to NPC treatment, and to aware the effective administrative timing of palbociclib with other chemodrugs. The findings give the basis for planning of the first-in-human clinical trials of palbociclib regimens in NPC patients.

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“…Thus, Palbociclib has not only a cytostatic effect but seemingly a potential cytotoxic effect on CMT cells. Although this observation contrasts to that for human BCa cells, which showed no apoptosis after prolonged Palbociclib treatment, cytotoxic potential for the CDK4/6 inhibitor was reported for human glioblastoma, hepatocellular carcinoma and T‐cell acute lymphoblastic leukaemia cells . Wang et al demonstrated that the pro‐apoptotic Palbociclib effect is associated with CDK6 expression in that Palbociclib induces apoptosis in cancer cells with high expression of CDK6, whereas cells with low CDK6 only show cell cycle arrest .…”

Section: Discussionmentioning

confidence: 90%

“…Thus, CF41 cells apparently resist the cytotoxic mechanisms of Palbociclib longer than P114 cells. Palbociclib induces apoptosis of tumour cells by interfering with enzymes regulating glucose metabolism in T‐ALL cells or activation of AMP‐activated protein kinase in hepatocellular carcinomas . Assuming that Palbociclib also affects the viability of CMT cells through such mechanisms, different susceptibilities of these target enzymes might be responsible for the delayed effect on P114 and CF41 cell viability.…”

Section: Discussionmentioning

confidence: 99%

In vitro study to assess the efficacy of CDK4/6 inhibitor Palbociclib (PD‐0332991) for treating canine mammary tumours

Schoos

Knab

Gabriel

et al. 2019

Vet Comparative Oncology

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Therapy of canine mammary tumours (CMTs) with classical antitumour drugs is problematic, so better therapeutic options are needed. Palbociclib (PD-0332991) is an innovative and effective anticancer drug for the treatment of breast cancer in women. Palbociclib is an inhibitor of cyclin-dependent kinase 4 (CDK4) and CDK6, which are key regulators of the cell cycle machinery and thus cell proliferation. In the present in vitro study, we investigated whether Palbociclib also represents a candidate drug to combat CMT. For this purpose, the effect of Palbociclib was analysed in P114 and CF41 cells, two CMT cell lines with an endogenous CDK4/6 co-expression. Incubation of P114 and CF41 cells with Palbociclib resulted in a dose-and timedependent loss of phosphorylated retinoblastoma protein (pRb), a classical CDK4/6 substrate within the cell cycle machinery. Moreover, treatment of CMT cells with Palbociclib-induced cell cycle arrest affected cell viability, prevented colony formation and impaired cell migration activity. Palbociclib also inhibited the growth of P114 and CF41 cell spheroids. Immunohistochemical analysis of canine patient samples revealed a consistent expression of CDK6 in different canine mammary carcinoma types, but an individual and tumour-specific expression pattern of phosphorylated pRb independent of the tumour grade. Together, our findings let us suggest that Palbociclib has antitumour effects on CMT cells and that canine patients may represent potential candidates for treatment with this CDK4/6 inhibitor. K E Y W O R D S canine mammary tumour, CDK4/6, cell cycle, migration, Palbociclib

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Palbociclib induces activation of AMPK and inhibits hepatocellular carcinoma in a CDK4/6‐independent manner

Cited by 61 publications

References 50 publications

Abemaciclib induces atypical cell death in cancer cells characterized by formation of cytoplasmic vacuoles derived from lysosomes

Abemaciclib induces atypical cell death in cancer cells characterized by formation of cytoplasmic vacuoles derived from lysosomes

Therapeutic Evaluation of Palbociclib and Its Compatibility with Other Chemotherapies in Primary and Recurrent Nasopharyngeal Carcinoma

In vitro study to assess the efficacy of CDK4/6 inhibitor Palbociclib (PD‐0332991) for treating canine mammary tumours

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