Tumor-Intrinsic and Tumor-Extrinsic Factors Impacting Hsp90- Targeted Therapy

Alarcon, Sylvia V.; Mollapour, Mehdi; Lee, M.-J.; Tsutsumi, Shinji; Lee, S.; Kim, Y.S.; Prince, Thomas; Apolo, Andrea B.; Giaccone, Giuseppe; Xu, Wanping; Neckers, Len; Trepel, Jane B.

doi:10.2174/156652412803306729

Cited by 46 publications

(36 citation statements)

References 161 publications

(162 reference statements)

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“…In the last decade, there have been 17 distinct Hsp90 inhibitors entered into clinical trials. Although no Hsp90 inhibitor has achieved regulatory approval, recently, there has been significant progress in Hsp90 inhibitor clinical development (40). Interestingly, we identified C086 as a novel Hsp90 inhibitor.…”

Section: Discussionmentioning

confidence: 92%

Dual Inhibition of Bcr-Abl and Hsp90 by C086 Potently Inhibits the Proliferation of Imatinib-Resistant CML Cells

Chen

et al. 2015

Clinical Cancer Research

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Purpose: Although tyrosine kinase inhibitors (TKI) such as imatinib provide an effective treatment against Bcr-Abl kinase activity in the mature cells of patients with chronic myelogenous leukemia (CML), TKIs probably cannot eradicate the leukemia stem cell (LSC) population. Therefore, alternative therapies are required to target both mature CML cells with wild-type (WT) or mutant Bcr-Abl and LSCs. To investigate the effect of C086, a derivative of curcumin, on imatinib-resistant cells, we explored its underlying mechanisms of Bcr-Abl kinase and heat shock protein 90 (Hsp90) function inhibition.Experimental Design: Biochemical assays were used to test ABL kinase activity; fluorescence measurements using recombinant NHsp90, Hsp90 ATPase assay, immunoprecipitation, and immunoblotting were applied to examine Hsp90 function. Colonyforming unit, long-term culture-initiating cells (LTC-IC), and flow cytometry were used to test CML progenitor and stem cells.Results: Biochemical assays with purified recombinant Abl kinase confirmed that C086 can directly inhibit the kinase activity of Abl, including WT and the Q252H, Y253F, and T315I mutations. Furthermore, we identified C086 as a novel Hsp90 inhibitor with the capacity to disrupt the Hsp90 chaperone function in CML cells. Consequently, it inhibited the growth of both imatinib-sensitive and -resistant CML cells. Interestingly, C086 has the capacity to inhibit LTC-ICs and to induce apoptosis in both CD34Conclusions: Dual suppression of Abl kinase activity and Hsp90 chaperone function by C086 provides a new therapeutic strategy for treating Bcr-Abl-induced leukemia resistant to TKIs.

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Section: Discussionmentioning

confidence: 92%

Dual Inhibition of Bcr-Abl and Hsp90 by C086 Potently Inhibits the Proliferation of Imatinib-Resistant CML Cells

Chen

et al. 2015

Clinical Cancer Research

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“…The overexpression of chaperones, such as HSP90, HSP27 and endoplasmin, has been identified in various forms of cancer, including lung (17,18), and has been reported to correlate with drug resistance (18). These chaperones induce tumor cell survival as they inhibit caspase activation (18), and thus we hypothesize that Umb may induce tumor apoptosis by removing suppression from caspases. Caspases are a family of endoproteases that are critical in apoptosis (programmed cell death) with a wide range of substrates, including vimentin (19).…”

Section: Discussionmentioning

confidence: 86%

“…Thus, this suggests that actin polymerization and cytoskeletal rearrangement were induced in the A549 cells in response to Umb. AHA1 (18), a co-chaperone that binds to HSP90, GAPDH (14) and stathemin (35) are well-known for their roles in tumor progression. Calreticulin is a Ca 2+ -binding chaperone and its cell surface expression is able to induce innate immune responses via ʻeat meʼ signals, which lead to capture of dying tumor cells by dendritic cells and macrophages (36).…”

Section: Discussionmentioning

confidence: 99%

Immune-associated proteins with potential in vivo anti-tumor activities are upregulated in lung cancer cells treated with umbelliprenin: A proteomic approach

et al. 2016

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Abstract. Umbelliprenin (Umb), a natural coumarin, has demonstrated anti-tumor activities, both in vitro and particularly in vivo, in several types of cancer, including lung cancer. The present study aimed to identify molecular targets of Umb using a high-throughput approach. Lung cancer cell lines, QU-DB (large-cell lung carcinoma) and A549 (adenocarcinoma), were treated with Umb. Differentially-expressed proteins were identified using two-dimensional electrophoresis coupled to mass spectrometry. In the QU-DB cells, differential expression of proteins, including downregulation of the tumorigenic protein heat shock protein 90 kDa and upregulation of the potential anti-tumor proteins Nipsnap1 and glycine-tRNA ligase (GRS), suggested that Umb is a strong anti-tumor compound. In the A549 cells, differential expression of proteins indicated possible contradictory effects of Umbregarding tumorigenesis, which included downregulation of the tumorigenic protein cyclophilin and the tumor suppressor MST, and upregulation of stathmin (tumorigenic) and calreticulin. Calreticulun, in addition to GRS in QU-DB cells, stimulates anti-tumor immune responses in vivo. To the best of our knowledge, the present study is the first to use a high-throughput approach to identify targets of Umb in cancer. These molecular targets suggested that Umb may exhibit stronger in vitro anti-tumor activity against the large-cell carcinoma model than the adenocarcinoma model. Furthermore, it has been reported that Umb exhibits higher cytotoxicity against QU-DB cells than A549 cells in vitro, and significant Umb anti-tumor activity against lung cancer in vivo, which is consistent with previously published literature. In each cell type, immune-associated molecules were upregulated, indicating that this naturally occurring compound exhibits marked anti-tumor activity in vivo. However, further studies that investigate the effect of Umb in different in vitro models of cancer are required.

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“…Based on the premise that structure dictates function, this relationship suggests that kinase activity is at least partially dependent on HSP90. Due to this relationship and the fact that a number of clinically relevant HSP90 inhibitors (H90Ins) currently exist (Alarcon et al 2012), the concept of targeting HSP90 as a way to broadly inhibit kinase activity in cancer deserves continued consideration (Whitesell and Lindquist 2005); (Trepel et al 2010); (Lu et al 2012a); (Barrott and Haystead 2013).…”

Section: Introductionmentioning

confidence: 99%

Combined HSP90 and kinase inhibitor therapy: Insights from The Cancer Genome Atlas

Schwartz

Scroggins

Zuehlke

et al. 2015

Cell Stress and Chaperones

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The merging of knowledge from genomics, cellular signal transduction and molecular evolution is producing new paradigms of cancer analysis. Protein kinases have long been understood to initiate and promote malignant cell growth and targeting kinases to fight cancer has been a major strategy within the pharmaceutical industry for over two decades. Despite the initial success of kinase inhibitors (KIs), the ability of cancer to evolve resistance and reprogram oncogenic signaling networks has reduced the efficacy of kinase targeting. The molecular chaperone HSP90 physically supports global kinase function while also acting as an evolutionary capacitor. The Cancer Genome Atlas (TCGA) has compiled a trove of data indicating that a large percentage of tumors overexpress or possess mutant kinases that depend on the HSP90 molecular chaperone complex. Moreover, the overexpression or mutation of parallel activators of kinase activity (PAKA) increases the number of components that promote malignancy and indirectly associate with HSP90. Therefore, targeting HSP90 is predicted to complement kinase inhibitors by inhibiting oncogenic reprogramming and cancer evolution. Based on this hypothesis, consideration should be given by both the research and clinical communities towards combining kinase inhibitors and HSP90 inhibitors (H90Ins) in combating cancer. The purpose of this perspective is to reflect on the current understanding of HSP90 and kinase biology as well as promote the exploration of potential synergistic molecular therapy combinations through the utilization of The Cancer Genome Atlas.

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Tumor-Intrinsic and Tumor-Extrinsic Factors Impacting Hsp90- Targeted Therapy

Cited by 46 publications

References 161 publications

Dual Inhibition of Bcr-Abl and Hsp90 by C086 Potently Inhibits the Proliferation of Imatinib-Resistant CML Cells

Dual Inhibition of Bcr-Abl and Hsp90 by C086 Potently Inhibits the Proliferation of Imatinib-Resistant CML Cells

Immune-associated proteins with potential in vivo anti-tumor activities are upregulated in lung cancer cells treated with umbelliprenin: A proteomic approach

Combined HSP90 and kinase inhibitor therapy: Insights from The Cancer Genome Atlas

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