Palbociclib induces cell senescence and apoptosis of gastric cancer cells by inhibiting the Notch pathway

Bi, Hengtai; Shang, Juan; Zou, Xiao; Xu, Jing; Han, Yu

doi:10.3892/ol.2021.12864

Cited by 17 publications

(8 citation statements)

References 39 publications

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“…The in-house-purified Dicer-TRBP complex processes pre-Let-7a and pre-miR-21 in minutes, similar to processing times observed within the cell (Figure S18), permitting inspection of the early (minutes) time points in the reaction, before The anti-proliferative activity of compounds 45 and 52 was determined in two cancer cell lines with high levels of miR-21, gastric adenocarcinoma (AGS), and pancreatic (ASPC1) cells. Compound 52 and Palbociclib (a positive control as a wellknown cancer inhibitory drug in both AGS 53 and ASPC1 cells, 54 which also contains the same pyridine-piperazine basic center as our molecules) each showed anti-proliferative activity at both concentrations tested in standard MTS assays conducted over 6 days. Cellular viability in the presence of either 52 or Palbociclib at 10 nmol/mL (Figure 5) or 5 nmol/ mL (Figure S19) decreased significantly after approximately 72−96 h of culture, but no significant effect was observed for compound 45.…”

Section: ■ Resultsmentioning

confidence: 94%

Drug-Like Small Molecules That Inhibit Expression of the Oncogenic MicroRNA-21

et al. 2023

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We report the discovery of drug-like small molecules that bind specifically to the precursor of the oncogenic and pro-inflammatory microRNA-21 with mid-nanomolar affinity. The small molecules target a local structure at the Dicer cleavage site and induce distinctive structural changes in the RNA, which correlate with specific inhibition of miRNA processing. Structurally conservative single nucleotide substitutions eliminate the conformational change induced by the small molecules, which is also not observed in other miRNA precursors. The most potent of these compounds reduces cellular proliferation and miR-21 levels in cancer cell lines without inhibiting kinases or classical receptors, while closely related compounds without this specific binding activity are inactive in cells. These molecules are highly ligand-efficient (MW < 330) and display specific biochemical and cellular activity by suppressing the maturation of miR-21, thereby providing an avenue toward therapeutic development in multiple diseases where miR-21 is abnormally expressed.

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Section: ■ Resultsmentioning

confidence: 94%

Drug-Like Small Molecules That Inhibit Expression of the Oncogenic MicroRNA-21

et al. 2023

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“…The anti-proliferative activity of compounds 45 and 52 was determined in two cancer cell lines characterized by high levels of miR-21, gastric adenocarcinoma AGS, and pancreatic ASPC1. Compound 52 and Palbociclib, a positive control as a well-known cancer inhibitory drug in both AGS 42 and ASPC1 cells 43 , both showed anti-proliferative activity at both concentrations tested in standard MTS assays conducted over 6 days. Cellular viability in the presence of either 52 or Palbociclib at 10 (Fig.…”

Section: Resultsmentioning

confidence: 99%

Drug-like small molecules that inhibit expression of the oncogenic microRNA-21

Shortridge

Chaubey

Zhang

et al. 2022

Preprint

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We report the discovery of a series of drug-like small molecules which bind specifically to the precursor of the oncogenic and pro-fibrotic microRNA-21 with mid-nanomolar affinity. These molecules are highly ligand-efficient (MW<330) and display specific biochemical and cellular activity by suppressing maturation of miR-21, thereby providing an avenue towards therapeutic intervention in multiple diseases where miR-21 is abnormally expressed. The small molecules target a local structure at the Dicer cleavage site and induce distinctive structural changes in the RNA which correlate with specific inhibition of miRNA processing. Structurally conservative single nucleotide substitutions eliminate the conformational change, which is not observed in other miRNA precursors. The most potent of these compounds reduces cellular proliferation and miR-21 levels in cancer cell lines without inhibiting kinases or classical receptors, while closely related compounds without this specific binding activity are inactive in cells.

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“…Pro-senescence anticancer therapies of clinical relevance can be exemplified by the recently developed cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors that interfere with the phosphorylation of the retinoblastoma protein (pRB) during the G1-S transition [91]. Palbociclib (PD 0332991), the prototypic CDK4/6 inhibitor, results in the arrest of cell-cycle progression and senescence induction in various in vitro and in vivo models [92][93][94][95]. Presently, Palbociclib is used in the treatment of patients with disseminated breast cancers that are positive for estrogen receptors [96], as well as patients with advanced gastric or esophageal cancer [97].…”

Section: Discussionmentioning

confidence: 99%

Palbociclib-Induced Cellular Senescence Is Modulated by the mTOR Complex 1 and Autophagy

Cayo,

Venturini,

Rebolledo-Mira

et al. 2023

IJMS

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Despite not dividing, senescent cells acquire the ability to synthesize and secrete a plethora of bioactive molecules, a feature known as the senescence-associated secretory phenotype (SASP). In addition, senescent cells often upregulate autophagy, a catalytic process that improves cell viability in stress-challenged cells. Notably, this “senescence-related autophagy” can provide free amino acids for the activation of mTORC1 and the synthesis of SASP components. However, little is known about the functional status of mTORC1 in models of senescence induced by CDK4/6 inhibitors (e.g., Palbociclib), or the effects that the inhibition of mTORC1 or the combined inhibition of mTORC1 and autophagy have on senescence and the SASP. Herein, we examined the effects of mTORC1 inhibition, with or without concomitant autophagy inhibition, on Palbociclib-driven senescent AGS and MCF-7 cells. We also assessed the pro-tumorigenic effects of conditioned media from Palbociclib-driven senescent cells with the inhibition of mTORC1, or with the combined inhibition of mTORC1 and autophagy. We found that Palbociclib-driven senescent cells display a partially reduced activity of mTORC1 accompanied by increased levels of autophagy. Interestingly, further mTORC1 inhibition exacerbated the senescent phenotype, a phenomenon that was reversed upon autophagy inhibition. Finally, the SASP varied upon inhibiting mTORC1, or upon the combined inhibition of mTORC1 and autophagy, generating diverse responses in cell proliferation, invasion, and migration of non-senescent tumorigenic cells. Overall, variations in the SASP of Palbociclib-driven senescent cells with the concomitant inhibition of mTORC1 seem to depend on autophagy.

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Palbociclib induces cell senescence and apoptosis of gastric cancer cells by inhibiting the Notch pathway

Cited by 17 publications

References 39 publications

Drug-Like Small Molecules That Inhibit Expression of the Oncogenic MicroRNA-21

Drug-Like Small Molecules That Inhibit Expression of the Oncogenic MicroRNA-21

Drug-like small molecules that inhibit expression of the oncogenic microRNA-21

Palbociclib-Induced Cellular Senescence Is Modulated by the mTOR Complex 1 and Autophagy

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