The novel, orally bioavailable HSP90 inhibitor NVP‐HSP990 induces cell cycle arrest and apoptosis in multiple myeloma cells and acts synergistically with melphalan by increased cleavage of caspases

Lamottke, Britta; Kaiser, Martin; Mieth, Maren; Heider, Ulrike; Gao, Zhenhai; Nikolova, Zariana; Jensen, Michael Rugaard; Sterz, Jan; Metzler, Ivana von; Sezer, Orhan

doi:10.1111/j.1600-0609.2012.01764.x

Cited by 24 publications

(19 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We observed decreases in the Akt levels and cleavage of Bid by BIIB021, followed by the activation of caspase-9. BIIB021 also activated caspase-8 in Molt-4 cells, consistent with the findings of a previous study [39] . Additionally, TPL has been shown to induce the loss of mitochondrial membrane potential and cytochrome c release, whereas caspase-9 knockout cells are resistant to TPL [16] .…”

Section: Discussionsupporting

confidence: 92%

Hsp90 inhibitor BIIB021 enhances triptolide-induced apoptosis of human T-cell acute lymphoblastic leukemia cells in vitro mainly by disrupting p53-MDM2 balance

Zhang

Chen

et al. 2013

Acta Pharmacol Sin

View full text Add to dashboard Cite

Aim: To investigate the effects of BIIB021, an inhibitor of heat shock protein 90 (Hsp90) alone or in combination with triptolide (TPL) on T-cell acute lymphoblastic leukemia (T-ALL) and the mechanisms of action. Methods: Human T-ALL cells line Molt-4 was examined. The cell viability was measured using MTT assay. Apoptotic cells were studied with Hoechst 33258 staining. Cell apoptosis and cell cycle were analyzed using flow cytometry with Annexin V/PI staining and PI staining, respectively. The levels of multiple proteins, including Akt, p65, CDK4/6, p18, Bcl-2 family proteins, MDM2, and p53, were examined with Western blotting. The level of MDM2 mRNA was determined using RT-PCR. Results: Treatment of Molt-4 cells with BIIB021 (50-800 nmol/L) inhibited the cell growth in a dose-dependent manner (the IC 50 value was 384.6 and 301.8 nmol/L, respectively, at 48 and 72 h). BIIB021 dose-dependently induced G 0 /G 1 phase arrest, followed by apoptosis of Molt-4 cells. Furthermore, BIIB021 increased the expression of p18, decreased the expression of CDK4/6, and activated the caspase pathway in Molt-4 cells. Moreover, BIIB021 (50-400 nmol/L) dose-dependently decreased the phospho-MDM2 and total MDM2 protein levels, but slightly increased the phospho-p53 and total p53 protein levels, whereas TPL (5-40 nmol/L) dosedependently enhanced p53 activation without affecting MDM2 levels. Co-treatment with BIIB021 and TPL showed synergic inhibition on Molt-4 cell growth. The co-treatment disrupted p53-MDM2 balance, thus markedly enhanced p53 activation. In addition, the co-treatment increased the expression of Bak and Bim, followed by increased activation of caspase-9. Conclusion: The combination of BIIB021 and TPL may provide a novel strategy for treating T-ALL by overcoming multiple mechanisms of apoptosis resistance.

show abstract

Section: Discussionsupporting

confidence: 92%

Hsp90 inhibitor BIIB021 enhances triptolide-induced apoptosis of human T-cell acute lymphoblastic leukemia cells in vitro mainly by disrupting p53-MDM2 balance

Zhang

Chen

et al. 2013

Acta Pharmacol Sin

View full text Add to dashboard Cite

show abstract

“…Lamottke et al (117) demonstrated that inhibition of Hsp90 by small molecular mass inhibitors induced cell death in multiple myeloma. They analyzed the effects of the novel, orally bioavailable Hsp90 inhibitor NVP-Hsp990 on multiple myeloma cell proliferation and survival.…”

Section: Combination Of Hsp90 Inhibitor With Second Therapymentioning

confidence: 99%

Hsp90 inhibitor as a sensitizer of cancer cells to different therapies (Review)

Solárová¹,

Mojžiš²,

Solár³

2014

Int J Oncol

View full text Add to dashboard Cite

Abstract. Hsp90 is a molecular chaperone that maintains the structural and functional integrity of various client proteins involved in signaling and many other functions of cancer cells. The natural inhibitors, ansamycins influence the Hsp90 chaperone function by preventing its binding to client proteins and resulting in their proteasomal degradation. Nand C-terminal inhibitors of Hsp90 and their analogues are widely tested as potential anticancer agents in vitro, in vivo as well as in clinical trials. It seems that Hsp90 competitive inhibitors target different tumor types at nanomolar concentrations and might have therapeutic benefit. On the contrary, some Hsp90 inhibitors increased toxicity and resistance of cancer cells induced by heat shock response, and through the interaction of survival signals, that occured as side effects of treatments, could be very effectively limited via combination of therapies. The aim of our review was to collect the data from experimental and clinical trials where Hsp90 inhibitor was combined with other therapies in order to prevent resistance as well as to potentiate the cytotoxic and/or antiproliferative effects.

show abstract

“…Additive effects of 17-AAG and SN-38, the active metabolite of IRN, have also been reported in p53-null HCT116 cells (Tse et al 2009). NVP-HSP990 has also shown synergy when used in combination with melphalan in multiple myeloma cells, inducing significantly more apoptosis than that induced by either agent alone (Lamottke et al 2012). …”

Section: Discussionmentioning

confidence: 99%

Re-examining HSPC1 inhibitors

Lee

Dempsey-Hibbert

Vimalachandran

et al. 2017

Cell Stress and Chaperones

View full text Add to dashboard Cite

HSPC1 is a critical protein in cancer development and progression, including colorectal cancer (CRC). However, clinical trial data reporting the effectiveness of HSPC1 inhibitors on several cancer types has not been as successful as predicted. Furthermore, some N-terminal inhibitors appear to be much more successful than others despite similar underlying mechanisms. This study involved the application of three N-terminal HSPC1 inhibitors, 17-DMAG, NVP-AUY922 and NVP-HSP990 on CRC cells. The effects on client protein levels over time were examined. HSPC1 inhibitors were also applied in combination with chemotherapeutic agents commonly used in CRC treatment (5-fluorouracil, oxaliplatin and irinotecan). As HSPA1A and HSPB1 have anti-apoptotic activity, gene-silencing techniques were employed to investigate the significance of these proteins in HSPC1 inhibitor and chemotherapeutic agent resistance. When comparing the action of the three HSPC1 inhibitors, there are distinct differences in the time course of important client protein degradation events. The differences between HSPC1 inhibitors were also reflected in combination treatment—17-DMAG was more effective compared with NVP-AUY922 in potentiating the cytotoxic effects of 5-fluorouracil, oxaliplatin and irinotecan. This study concludes that there are distinct differences between N-terminal HSPC1 inhibitors, despite their common mode of action. Although treatment with each of the inhibitors results in significant induction of the anti-apoptotic proteins HSPA1A and HSPB1, sensitivity to HSPC1 inhibitors is not improved by gene silencing of HSPA1A or HSPB1. HSPC1 inhibitors potentiate the cytotoxic effects of chemotherapeutic agents in CRC, and this approach is readily available to enter clinical trials. From a translational point of view, there may be great variability in sensitivity to the inhibitors between individual patients.

show abstract

The novel, orally bioavailable HSP90 inhibitor NVP‐HSP990 induces cell cycle arrest and apoptosis in multiple myeloma cells and acts synergistically with melphalan by increased cleavage of caspases

Cited by 24 publications

References 31 publications

Hsp90 inhibitor BIIB021 enhances triptolide-induced apoptosis of human T-cell acute lymphoblastic leukemia cells in vitro mainly by disrupting p53-MDM2 balance

Hsp90 inhibitor BIIB021 enhances triptolide-induced apoptosis of human T-cell acute lymphoblastic leukemia cells in vitro mainly by disrupting p53-MDM2 balance

Hsp90 inhibitor as a sensitizer of cancer cells to different therapies (Review)

Re-examining HSPC1 inhibitors

Contact Info

Product

Resources

About