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

Solárová, Zuzana; Mojžiš, Ján; Solár, Peter

doi:10.3892/ijo.2014.2791

Cited by 37 publications

(25 citation statements)

References 235 publications

(55 reference statements)

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“…Eukaryotic initiation factor 2 ER Endoplasmic reticulum ERK1/2 Extracellular signal-regulated kinase 1/2 GRP78/BiP Glucose-regulated protein 78…”

Section: Ddit3mentioning

confidence: 99%

“…N-terminal domain inhibitors act by disrupting the interaction between ATP and ATP-binding pocket, and they restrain HSP90 in the ADP-bound state that leads to ubiquitylation and subsequent proteasomal degradation of the client proteins [77]. In turn, C-terminal domain inhibitors destabilize the chaperone complex and induce a release of co-chaperones and degradation of client proteins [78,79]. Inhibitors of the middle domain of HSP90 directly or allosterically disrupt interactions between HSP90 and C-terminal binding proteins [80].…”

Section: Hsp90 Inhibitorsmentioning

confidence: 99%

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Inhibitors of HSP90 in melanoma

Mielczarek-Lewandowska

Hartman

Czyż

2019

Apoptosis

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HSP90 (heat shock protein 90) is an ATP-dependent molecular chaperone involved in a proper folding and maturation of hundreds of proteins. HSP90 is abundantly expressed in cancer, including melanoma. HSP90 client proteins are the key oncoproteins of several signaling pathways controlling melanoma development, progression and response to therapy. A number of natural and synthetic compounds of different chemical structures and binding sites within HSP90 have been identified as selective HSP90 inhibitors. The majority of HSP90-targeting agents affect N-terminal ATPase activity of HSP90. In contrast to N-terminal inhibitors, agents interacting with the middle and C-terminal domains of HSP90 do not induce HSP70dependent cytoprotective response. Several inhibitors of HSP90 were tested against melanoma in pre-clinical studies and clinical trials, providing evidence that these agents can be considered either as single or complementary therapeutic strategy. This review summarizes current knowledge on the role of HSP90 protein in cancer with focus on melanoma, and provides an overview of structurally different HSP90 inhibitors that are considered as potential therapeutics for melanoma treatment.

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“…Eukaryotic initiation factor 2 ER Endoplasmic reticulum ERK1/2 Extracellular signal-regulated kinase 1/2 GRP78/BiP Glucose-regulated protein 78…”

Section: Ddit3mentioning

confidence: 99%

Section: Hsp90 Inhibitorsmentioning

confidence: 99%

Inhibitors of HSP90 in melanoma

Mielczarek-Lewandowska

Hartman

Czyż

2019

Apoptosis

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“…To further determine the streaming relationship between the two signalling proteins, we applied their pharmacological inhibitor on each other. According to our results, the HSP90 inhibitor [21], GA, blocked the induced IKK/I κ B/p65 activation, while the NF- κ B/p65 inhibitor [12], JSH-23, failed in inhibiting HSP90 upregulation when oxidative stress happens in NSCs. It suggested an upper-stream role of HSP90 to NF- κ B/p65 in NSCs oxidative stress.…”

Section: Discussionmentioning

confidence: 76%

Inhibition of HSP90 Promotes Neural Stem Cell Survival from Oxidative Stress through Attenuating NF-κB/p65 Activation

Liu

Jiang

et al. 2016

Oxidative Medicine and Cellular Longevity

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Stem cell survival after transplantation determines the efficiency of stem cell treatment, which develops as a novel potential therapy for several central nervous system (CNS) diseases in recent decades. The engrafted stem cells face the damage of oxidative stress, inflammation, and immune response at the lesion point in host. Among the damaging pathologies, oxidative stress directs stem cells to apoptosis and even death through several signalling pathways and DNA damage. However, the in-detail mechanism of stem cell survival from oxidative stress has not been revealed clearly. Here, in this study, we used hydrogen peroxide (H2O2) to induce the oxidative damage on neural stem cells (NSCs). The damage was in consequence demonstrated involving the activation of heat shock protein 90 (HSP90) and NF-κB/p65 signalling pathways. Further application of the pharmacological inhibitors, respectively, targeting at each signalling indicated an upper-stream role of HSP90 upon NF-κB/p65 on NSCs survival. Preinhibition of HSP90 with the specific inhibitor displayed a significant protection on NSCs against oxidative stress. In conclusion, inhibition of HSP90 would attenuate NF-κB/p65 activation by oxidative induction and promote NSCs survival from oxidative damage. The HSP90/NF-κB mechanism provides a new evidence on rescuing NSCs from oxidative stress and also promotes the stem cell application on CNS pathologies.

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“…GRP94, the endoplasmic reticulum paralog of HSP90, is vital to protein quality control of proteins targeted for membrane localization and secretion [66], as well as in optimized ER stress responses [67]. HSP90 has a significant history as a target of cancer therapy [68] that has become modified to include the potential of HSP90 therapeutics as sensitizers in combination therapies [69]. Moreover, other organellar-specific HSP90 family members are topics of discussion for therapeutic targeting, as well [70], implying that GRP94 could be a valuable focus for treatment.…”

Section: Discussionmentioning

confidence: 99%

HSP90 inhibitors in the context of heat shock and the unfolded protein response: effects on a primary canine pulmonary adenocarcinoma cell line*

Graner

Hellwinkel

Lencioni

et al. 2016

International Journal of Hyperthermia

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Background Agents targeting HSP90 and GRP94 are seldom tested in stressed contexts such as heat shock (HS) or the unfolded protein response (UPR). Tumor stress often activates HSPs and the UPR as pro-survival mechanisms. This begs the question of stress effects on chemotherapeutic efficacy, particularly with drugs targeting chaperones such as HSP90 or GRP94. We tested the utility of several HSP90 inhibitors, including PU-H71 (targeting GRP94), on a primary canine lung cancer line under HS/UPR stress compared to control conditions. Methods We cultured canine bronchoalveolar adenocarcinoma cells that showed high endogenous HSP90 and GRP94 expression; these levels substantially increased upon HS or UPR induction. We treated cells with HSP90 inhibitors 17-DMAG, 17-AAG, or PU-H71 under standard conditions, HS, or UPR. Cell viability/survival were assayed. Antibody arrays measured intracellular signalling and apoptosis profiles. Results HS and UPR had varying effects on cells treated with different HSP90 inhibitors; in particular, HS and UPR promoted resistance to inhibitors in short-term assays, but combinations of UPR stress and PU-H571 showed potent cytotoxic activity in longer-term assays. Array data indicated altered signalling pathways, with apoptotic and pro-survival implications. UPR induction+dual targeting of HSP90 and GRP94 swayed the balance toward apoptosis. Conclusion Cellular stresses, endemic to tumors, or interventionally inducible, can deflect or enhance chemo-efficacy, particularly with chaperone-targeting drugs. Stress is likely not held accountable when testing new pharmacologics or assessing currently-used drugs. A better understanding of stress impacts on drug activities should be critical in improving therapeutic targeting and in discerning mechanisms of drug resistance.

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

Cited by 37 publications

References 235 publications

Inhibitors of HSP90 in melanoma

Inhibitors of HSP90 in melanoma

Inhibition of HSP90 Promotes Neural Stem Cell Survival from Oxidative Stress through Attenuating NF-κB/p65 Activation

HSP90 inhibitors in the context of heat shock and the unfolded protein response: effects on a primary canine pulmonary adenocarcinoma cell line*

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