Evodiamine inhibits both stem cell and non-stem-cell populations in human cancer cells by targeting heat shock protein 70

Hyun, Sangwon; Le, Huong Thuy; Min, Hye‐Young; Pei, Honglan; Lim, Yijae; Song, Injae; Yen, Nguyen Thi Hai; Hong, Suckchang; Han, Byung Woo; Lee, Ho‐Young

doi:10.7150/thno.49876

Cited by 38 publications

(18 citation statements)

References 74 publications

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“…Similarly, in prostrate cancer, selectively targeting CSCs with the de-methylating agent 5-azathioprine or the signalling inhibitor γ-tocotrienol in combination with selectively targeting NSCCs with an enhancer of androgen receptor degradation leads to significant synergy in tumour suppression and therapeutic efficacy [51]. Another promising trend in currently ongoing preclinical research lies in identifying suitable single substances which target both CSCs and NSCCs in parallel [52][53][54].…”

Section: Discussionmentioning

confidence: 99%

On tumoural growth and treatment under cellular dedifferentiation

Fischer

Blüthgen

2022

Preprint

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Differentiated cancer cells may regain stem cell characteristics; however, the effects of such a cellular dedifferentiation on tumoural growth and treatment are currently understudied. Thus, we here extend a mathematical model of cancer stem cell (CSC) driven tumour growth to also include dedifferentiation. We show that dedifferentiation increases the likelihood of tumorigenenis and the speed of tumoural growth, both modulated by the proliferative potential of the non-stem cancer cells (NSCCs). We demonstrate that dedifferentiation also may lead to treatment evasion, especially when a treatment solely targets CSCs. Conversely, targeting both CSCs and NSCCs in parallel is shown to be more robust to dedifferentiation. Despite dedifferentiation, perturbing CSC-related parameters continues to exert the largest relative effect on tumoural growth; however, we show the existence of synergies between specific CSC- and NSCC-directed treatments which cause superadditive reductions of tumoural growth. Overall, our study demonstrates various effects of dedifferentiation on growth and treatment of tumoural lesions, and we anticipate our results to be helpful in guiding future molecular and clinical research on limiting tumoural growth in vivo.

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Section: Discussionmentioning

confidence: 99%

On tumoural growth and treatment under cellular dedifferentiation

Fischer

Blüthgen

2022

Preprint

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“…Cloning and purification of recombinant Hsp90 and Hsp70 proteins and immunoprecipitation and pulldown assays to determine the interaction between NCT-80 and Hsp90 were performed as described in our previous reports 28 , 29 …”

Section: Methodsmentioning

confidence: 99%

“…DARTS was performed according to the previously published procedure with some modifications 29 . Briefly, 35 μg of purified Hsp90 and Hsp70 proteins were treated with vehicle (DMSO) or 5 μM NCT-80 (final 1% DMSO) for 30 min at 4 °C, and then incubated with proteinase K (proteinase K:protein ratio 1:10 and 1:40) for 15 min at room temperature.…”

Section: Methodsmentioning

confidence: 99%

A novel C-terminal heat shock protein 90 inhibitor that overcomes STAT3-Wnt-β-catenin signaling-mediated drug resistance and adverse effects

Lee¹,

Min²,

Yong³

et al. 2022

Theranostics

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Rationale: The heat shock protein (Hsp) system plays important roles in cancer stem cell (CSC) and non-CSC populations. However, limited efficacy due to drug resistance and toxicity are obstacles to clinical use of Hsp90 inhibitors, suggesting the necessity to develop novel Hsp90 inhibitors overcoming these limitations. Methods: The underlying mechanism of resistance to Hsp90 inhibitors was investigated by colony formation assay, sphere formation assay, western blot analysis, and real-time PCR. To develop anticancer Hsp90 inhibitors that overcome the signal transducer and activator of transcription 3 (STAT3)-mediated resistance, we synthesized and screened a series of synthetic deguelin-based compounds in terms of inhibition of colony formation, migration, and viability of non-small cell lung cancer (NSCLC) cells and toxicity to normal cells. Regulation of Hsp90 by the selected compound NCT-80 [5-methoxy-N-(3-methoxy-4-(2-(pyridin-3-yl)ethoxy)phenyl)-2,2-dimethyl-2H-chromene-6-carboxamide] was investigated by immunoprecipitation, drug affinity responsive target stability assay, binding experiments using ATP-agarose beads and biotinylated drug, and docking analysis. The antitumor, antimetastatic, and anti-CSC effects of NCT-80 were examined in vitro and in vivo using various assays such as MTT, colony formation, and migration assays and flow cytometric analysis and tumor xenograft models. Results: We demonstrated a distinct mechanism in which Hsp90 inhibitors that block N-terminal ATP-binding pocket causes transcriptional upregulation of Wnt ligands through Akt- and ERK-mediated activation of STAT3, resulting in NSCLC cell survival in an autocrine or paracrine manner. In addition, NCT-80 effectively reduced viability, colony formation, migration, and CSC-like phenotypes of NSCLC cells and their sublines with acquired resistance to anticancer drugs by inducing apoptosis and inhibiting epithelial-mesenchymal transition and the growth of NSCLC patient-derived xenograft tumors without overt toxicity. With regards to mechanism, NCT-80 directly bound to the C-terminal ATP-binding pocket of Hsp90, disrupting the interaction between Hsp90 and STAT3 and degrading STAT3 protein. Moreover, NCT-80 inhibited chemotherapy- and EGFR TKI-induced programmed cell death ligand 1 expression and potentiated the antitumor effect of chemotherapy in the LLC-Luc allograft model. Conclusions: These data indicate the potential of STAT3/Wnt signaling pathway as a target to overcome resistance to Hsp90 inhibitors and NCT-80 as a novel Hsp90 inhibitor that targets both CSCs and non-CSCs in NSCLC.

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“…HSPs are a family of proteins that respond to stress events and function as chaperones ( 137 ). HSPs are upregulated by heat shock factors (HSFs) during environmental stress conditions ( 138 ).…”

Section: The Tumor Microenvironment (Tme) and Anoikis Resistancementioning

confidence: 99%

Anoikis resistance in diffuse glioma: The potential therapeutic targets in the future

Zhu

Fang

et al. 2022

Front. Oncol.

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Glioma is the most common malignant intracranial tumor and exhibits diffuse metastasis and a high recurrence rate. The invasive property of glioma results from cell detachment. Anoikis is a special form of apoptosis that is activated upon cell detachment. Resistance to anoikis has proven to be a protumor factor. Therefore, it is suggested that anoikis resistance commonly occurs in glioma and promotes diffuse invasion. Several factors, such as integrin, E-cadherin, EGFR, IGFR, Trk, TGF-β, the Hippo pathway, NF-κB, eEF-2 kinase, MOB2, hypoxia, acidosis, ROS, Hsp and protective autophagy, have been shown to induce anoikis resistance in glioma. In our present review, we aim to summarize the underlying mechanism of resistance and the therapeutic potential of these molecules.

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Evodiamine inhibits both stem cell and non-stem-cell populations in human cancer cells by targeting heat shock protein 70

Cited by 38 publications

References 74 publications

On tumoural growth and treatment under cellular dedifferentiation

On tumoural growth and treatment under cellular dedifferentiation

A novel C-terminal heat shock protein 90 inhibitor that overcomes STAT3-Wnt-β-catenin signaling-mediated drug resistance and adverse effects

Anoikis resistance in diffuse glioma: The potential therapeutic targets in the future

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