Targeting CDK9 by wogonin and related natural flavones potentiates the anti‐cancer efficacy of the Bcl‐2 family inhibitor ABT‐263

Polier, Gernot; Giaisi, Marco; Köhler, Rebecca; Müller, Wolfgang W.; Lutz, Christoph; Buss, Eike C.; Krammer, Peter H.; Li‐Weber, Min

doi:10.1002/ijc.29009

Cited by 51 publications

(35 citation statements)

References 53 publications

(99 reference statements)

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“…As expected, apoptosis induced by cotreatment with LS-007 and ABT-199 was remarkable without reaching the dosages inducing obvious apoptosis by LS-007 or ABT-199 alone, indicating stronger efficacy with less toxicity at the same time. In contrast to a previous study, in which the CDK9 inhibitor wogonin potentiated the anti-cancer activity of the Bcl-2 family inhibitor ABT-263 mainly through downregulating the Mcl-1 levels [33] , maximal suppression of XIAP, other than through Mcl-1, was observed when LS-007 was combined with ABT-199. As an anti-apoptotic protein, the synergistic inhibition of XIAP may contribute to the greatly increased cells in apoptosis.…”

Section: Discussioncontrasting

confidence: 50%

“…As expected, ABT-199 or LS-007 alone modestly reduced XIAP expression, whereas the maximal suppression of XIAP was observed in dual-treated cells. Up-regulation of Mcl-1 may mediate resistance to Bcl-2 inhibitors in many tumors [33] . In the present study, ABT-199 alone slightly elevated the level of Mcl-1, and LS-007 reversed the up-regulation in dual-treated cells.…”

Section: Ls-007 Down-regulates Both the Transcriptional And Protein Lmentioning

confidence: 99%

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Antitumor action of CDK inhibitor LS-007 as a single agent and in combination with ABT-199 against human acute leukemia cells

et al. 2016

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Aim: LS-007 is a CDK inhibitor, which exhibits potent antitumor activity against chronic lymphocytic leukemia and ovarian cancer cells. In this study, we further evaluated the antitumor activity of LS-007 alone and in combination with a Bcl-2 inhibitor ABT-199 in acute leukemia (AL) cells. Methods: Cell viability was detected using resazurin assay, and cell apoptosis was examined using Annexin V/PI double staining and flow cytometry. The inhibition of LS-007 on kinases was evaluated with the mobility shift assay or ELISA. The expression of relevant signaling molecules was assessed using Western blotting and RT-PCR. Primary lymphocytes from patients with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) were separated using Ficoll-Paque PLUS. Results: LS-007 inhibited the proliferation of 6 AL cell lines with IC 50 values of 100-200 nmol/L, and decreased the survival of ALL and AML patient-derived lymphocytes with mean LD 50 value of 67 and 102 nmol/L, respectively. In kinase assays in vitro, LS-007 was more selective for the CDK family, inhibiting CDK2, CDK9, CDK1 and CDK4 at low nanomolar concentrations. In HL-60 and CCRF-CEM cells, LS-007 (0.1-0.4 μmol/L) dose-dependently induced cell apoptosis predominantly through CDK9 inhibition-related dephosphorylation at the ser2 residue of RNA pol II and the corresponding depletion of anti-apoptotic proteins, especially Mcl-1 and XIAP. LS-007 (0.2 and 0.4 μmol/L) also induced cell apoptosis in the patient-derived lymphocytes. In HL-60, CCRF-CEM and Molt-4 cells, combined application of LS-007 with ABT-199 (1 or 2 μmol/L) markedly increased cell apoptosis with a maximal decrease in the XIAP levels as compared with either drug used alone. Conclusion: CDK inhibitor LS-007 potently inhibits the established human AL cell lines and primary AL blasts, and it also shows remarkable synergy with Bcl-2 inhibitor

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Section: Discussioncontrasting

confidence: 50%

Section: Ls-007 Down-regulates Both the Transcriptional And Protein Lmentioning

confidence: 99%

Antitumor action of CDK inhibitor LS-007 as a single agent and in combination with ABT-199 against human acute leukemia cells

et al. 2016

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“…Thus, CDK8 and CDK9 control different steps in RNA Pol II-mediated transcription. CDK9 has also been suggested to be a useful therapeutic target, and CDK9 inhibitors may be selectively cytotoxic to cancer cells compared with normal cells (De Falco and Giordano, 2002;Nowicki and Walkinshaw, 2010;Polier et al, 2011Polier et al, , 2015Liu et al, 2012;Wang et al, 2014).…”

Section: Non-cell Cycle Cdks As Drug Targetsmentioning

confidence: 99%

Cyclin-Dependent Kinase Inhibitors as Anticancer Therapeutics

et al. 2015

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Cyclin-dependent kinases (CDKs) have been considered promising drug targets for a number of years, but most CDK inhibitors have failed rigorous clinical testing. Recent studies demonstrating clear anticancer efficacy and reduced toxicity of CDK4/6 inhibitors such as palbociclib and multi-CDK inhibitors such as dinaciclib have rejuvenated the field. Favorable results with palbociclib and its recent U.S. Food and Drug Administration approval demonstrate that CDK inhibitors with narrow selectivity profiles can have clinical utility for therapy based on individual tumor genetics. A brief overview of results obtained with ATPcompetitive inhibitors such as palbociclib and dinaciclib is presented, followed by a compilation of new avenues that have been pursued toward the development of novel, non-ATPcompetitive CDK inhibitors. These creative ways to develop CDK inhibitors are presented along with crystal structures of these agents complexed with CDK2 to highlight differences in their binding sites and mechanisms of action. The recent successes of CDK inhibitors in the clinic, combined with the potential for structure-based routes to the development of non-ATP-competitive CDK inhibitors, and evidence that CDK inhibitors may have use in suppressing chromosomal instability and in synthetic lethal drug combinations inspire optimism that CDK inhibitors will become important weapons in the fight against cancer.

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“…Furthermore, wogonin and the structurally related natural flavones apigenin, chrysin and luteolin, bind directly to cyclin-dependent kinase 9 (CDK9) presumably to the ATP-binding pocket, and block phosphorylation of the carboxy-terminal domain of RNA polymerase II, leading to reduced RNA synthesis and subsequently rapid downregulation of the short-lived Mcl-1. Furthermore, wogonin preferentially inhibits CDK9 in malignant lymphocytes compared with normal lymphocytes [89,90]. More recently, an in vivo study with intraperitoneal injection of murine leukemia WEHI-3 cells into normal BALB/c mice demonstrated that wogonin increases the survival rate and the body weight of leukemic mice by increasing the populations of T-and B-cells [91].…”

Section: Wogonin and Wogonosidementioning

confidence: 99%

Natural products against hematological malignancies and identification of their targets

Xü

Liu

et al. 2015

Sci. China Life Sci.

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Targeting CDK9 by wogonin and related natural flavones potentiates the anti‐cancer efficacy of the Bcl‐2 family inhibitor ABT‐263

Cited by 51 publications

References 53 publications

Antitumor action of CDK inhibitor LS-007 as a single agent and in combination with ABT-199 against human acute leukemia cells

Antitumor action of CDK inhibitor LS-007 as a single agent and in combination with ABT-199 against human acute leukemia cells

Cyclin-Dependent Kinase Inhibitors as Anticancer Therapeutics

Natural products against hematological malignancies and identification of their targets

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