Effects of amiloride on physiological activity of stem cells of human lung cancer and possible mechanism

Zhang, Hengshuo; Peng, Caixia; Huang, He; Lai, Yongxin; Hu, Chenchen; Li, Fēi; Wang, Degui

doi:10.1016/j.bbrc.2018.06.138

Cited by 11 publications

(4 citation statements)

References 22 publications

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“…However, numerous studies have attributed pharmacological effects to a specific target of interest following treatment with amiloride or an analog without consideration of possible off-target effects [41][42][43]. In the cancer field alone, there are a several examples whereby effects have been ascribed to inhibition of either uPA [44][45][46] or NHE1 [47][48][49] without controlling for possible effects from the other target. The situation is further confounded in studies that use amiloride as a "specific inhibitor" due to possible effects from ENaC.…”

Section: Discussionmentioning

confidence: 99%

Screening of 5- and 6-Substituted Amiloride Libraries Identifies Dual-uPA/NHE1 Active and Single Target-Selective Inhibitors

Buckley

Kumar

Aboelela

et al. 2021

IJMS

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The K+-sparing diuretic amiloride shows off-target anti-cancer effects in multiple rodent models. These effects arise from the inhibition of two distinct cancer targets: the trypsin-like serine protease urokinase-type plasminogen activator (uPA), a cell-surface mediator of matrix degradation and tumor cell invasiveness, and the sodium-hydrogen exchanger isoform-1 (NHE1), a central regulator of transmembrane pH that supports carcinogenic progression. In this study, we co‑screened our library of 5- and 6-substituted amilorides against these two targets, aiming to identify single-target selective and dual-targeting inhibitors for use as complementary pharmacological probes. Closely related analogs substituted at the 6-position with pyrimidines were identified as dual-targeting (pyrimidine 24 uPA IC50 = 175 nM, NHE1 IC50 = 266 nM, uPA selectivity ratio = 1.5) and uPA-selective (methoxypyrimidine 26 uPA IC50 = 86 nM, NHE1 IC50 = 12,290 nM, uPA selectivity ratio = 143) inhibitors, while high NHE1 potency and selectivity was seen with 5-morpholino (29 NHE1 IC50 = 129 nM, uPA IC50 = 10,949 nM; NHE1 selectivity ratio = 85) and 5-(1,4-oxazepine) (30 NHE1 IC50 = 85 nM, uPA IC50 = 5,715 nM; NHE1 selectivity ratio = 67) analogs. Together, these amilorides comprise a new toolkit of chemotype-matched, non-cytotoxic probes for dissecting the pharmacological effects of selective uPA and NHE1 inhibition versus dual-uPA/NHE1 inhibition.

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Section: Discussionmentioning

confidence: 99%

Screening of 5- and 6-Substituted Amiloride Libraries Identifies Dual-uPA/NHE1 Active and Single Target-Selective Inhibitors

Buckley

Kumar

Aboelela

et al. 2021

IJMS

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“…Previous studies have established that the inhibition of extracellular vesicle (EV) secretion using diuretic agents like Amiloride (AME) or small molecule inhibitors such as GW4869 can effectively reduce the growth of pancreatic, lung, and colon cancers [38][39][40][41][42]. However, the potential impact of inhibiting proteins involved in EV secretion pathways or blocking exosome secretion as a means of prevention or oncotherapy in the context of obesity-mediated endometrial cancer (EC) has not been previously explored.…”

Section: Discussionmentioning

confidence: 99%

Exploring the role of obesity-induced extracellular vesicles secretion and associated oncogenic proteins in endometrial cancer pathogenesis.

Selvendiran,

Sakaue,

Zingarelli

et al. 2024

Preprint

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Endometrial cancer (EC) is the leading gynecologic malignancy in the United States with obesity implicated in 57% of cases. This research delves into the molecular complexities of extracellular vesicle (EV) secretion as carriers of oncogenic protein expression and their involvement in obesity-mediated EC. An understanding of these mechanisms is pivotal for unraveling pathways relevant to obesity-associated EC, thereby guiding the development of innovative prevention and treatment strategies. Our investigation revealed a significant increase in EV secretion carrying oncogenic proteins (TMEM205, STAT5, and FAS) in adipose and uterine tissues/serum samples from obese EC patients compared to their non-obese counterparts. We identified alterations in EV-regulating proteins (Rab7, Rab11, and Rab27a) in obesity-mediated EC patient adipose and uterine samples. Through a 24-week analysis of the effects of a 45% kcal high-fat diet (HFD) on mice, we observed heightened body weight, increased adipose tissue, enlarged uterine horns, and heightened inflammation in the HFD group. This correlated with elevated levels of EV secretion and increased expression of oncogenic proteins TMEM205, FAS, and STAT5, while the tumor suppressor gene PIAS3 was downregulated in adipose and uterine tissues in HFD treated mice. Furthermore, our study confirmed that adipocyte derived EVs increased EC cell proliferation and migration. Additionally, we identified that the small molecule inhibitors (HO-3867) or Metformin inhibited EV secretion in vitro and in vivo, demonstrating significant inhibition of high glucose or adipocyte-mediated EC cell proliferation and a reduction in body weight and adipose tissue accumulation when administered to HFD mice. Moreover, HO-3867 or Metformin treatment inhibits HFD induced hyperplasia by altered the expression of EV-regulated proteins (Rab7, Rab11, and Rab27a) and decreased oncogenic protein expression (TMEM205, FAS and STAT5) levels. This study provides critical insights into the mechanisms supporting obesity-mediated EV secretion with oncogenic protein expression, shedding light on their role in EC pathogenesis. Additionally, it offers pre-clinical evidence supporting the initiation of novel studies for EV-targeted therapies aimed at preventing obesity-mediated EC.

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“…Increased uPA expression and activity promote tumour cell invasion into surrounding tissues by stimulating the breakdown of BM and ECM (Andreasen et al 1997;Didiasova et al 2014;Magill et al 1999). Dysregulated activity of the uPAS is also implicated in tumour cell proliferation, migration and metastasis (Kugaevskaya et al 2018;Mahmood et al 2018;Zhang et al 2018) and contributes to poor prognosis (Su et al 2016) and progression in various cancers including melanoma (Cho et al 2019), hepatocellular carcinoma (HCC) (Wei et al 2019), lung adenocarcinoma (Zhu et al 2020), neuroendocrine (Özdirik et al 2020), oral (Wyganowska-Świątkowska & Jankun 2015), gastric (Brungs et al 2017;Kaneko et al 2003), ovarian (van der Burg et al 1996), breast (Tang & Han 2013;Xing & Rabbani 1996), prostate (Kimura et al 2020), colorectal (Yang et al 2000) and bladder cancers (Hasui & Osada 1997;Iwata et al 2019). In breast cancer, the uPAS has been identified as the most reliable independent prognostic marker of poor prognosis (Banys-Paluchowski et al 2019;Bouchet et al 1994;Duffy et al 1988;Foekens et al 2000;Harbeck et al 2002).…”

Section: The Urokinase Plasminogen Activation System (Upas)mentioning

confidence: 99%

Urokinase plasminogen activator as an anti-metastasis target: inhibitor design principles, recent amiloride derivatives, and issues with human/mouse species selectivity

et al. 2022

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Effects of amiloride on physiological activity of stem cells of human lung cancer and possible mechanism

Cited by 11 publications

References 22 publications

Screening of 5- and 6-Substituted Amiloride Libraries Identifies Dual-uPA/NHE1 Active and Single Target-Selective Inhibitors

Screening of 5- and 6-Substituted Amiloride Libraries Identifies Dual-uPA/NHE1 Active and Single Target-Selective Inhibitors

Exploring the role of obesity-induced extracellular vesicles secretion and associated oncogenic proteins in endometrial cancer pathogenesis.

Urokinase plasminogen activator as an anti-metastasis target: inhibitor design principles, recent amiloride derivatives, and issues with human/mouse species selectivity

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