Itraconazole inhibits invasion and migration of pancreatic cancer cells by suppressing TGF-β/SMAD2/3 signaling

Chen, Ke; Liu, Cheng; Qian, Weikun; Jiang, Zhengdong; Sun, Liankang; Zhao, Yong; Zhou, Yongsheng; Zhao, Lizhi; Wang, Pengli; Duan, Wanxing; Ma, Qingyong; Yang, Wei

doi:10.3892/or.2018.6281

Cited by 16 publications

(17 citation statements)

References 36 publications

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“…In addition, an in vitro study showed that itraconazole has anticancer effects on oral squamous cell carcinoma through proteins expression downregulation of Hedgehog pathway by inhibiting cell proliferation and migration [ 196 ]. Another in vitro study in pancreatic cancer demonstrated that itraconazole inhibit viability, induce apoptosis and suppress invasion and migration by impaired transforming growth factor beta (TGF-β)/mothers against decapentaplegic homolog 2/3 (SMAD2/3) signalling [ 197 ]. In oesophageal cancer, it was demonstrated that itraconazole inhibits cell growth through activating AMPK signalling [ 198 , 199 ].…”

Section: Drug Repurposing For Ovarian Cancer Therapymentioning

confidence: 99%

Recycling the Purpose of Old Drugs to Treat Ovarian Cancer

Nunes

Abreu

Bartosch

et al. 2020

IJMS

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The main challenge in ovarian cancer treatment is the management of recurrences. Facing this scenario, therapy selection is based on multiple factors to define the best treatment sequence. Target therapies, such as bevacizumab and polymerase (PARP) inhibitors, improved patient survival. However, despite their achievements, ovarian cancer survival remains poor; these therapeutic options are highly costly and can be associated with potential side effects. Recently, it has been shown that the combination of repurposed, conventional, chemotherapeutic drugs could be an alternative, presenting good patient outcomes with few side effects and low costs for healthcare institutions. The main aim of this review is to strengthen the importance of repurposed drugs as therapeutic alternatives, and to propose an in vitro model to assess the therapeutic value. Herein, we compiled the current knowledge on the most promising non-oncological drugs for ovarian cancer treatment, focusing on statins, metformin, bisphosphonates, ivermectin, itraconazole, and ritonavir. We discuss the primary drug use, anticancer mechanisms, and applicability in ovarian cancer. Finally, we propose the use of these therapies to perform drug efficacy tests in ovarian cancer ex vivo cultures. This personalized testing approach could be crucial to validate the existing evidences supporting the use of repurposed drugs for ovarian cancer treatment.

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Section: Drug Repurposing For Ovarian Cancer Therapymentioning

confidence: 99%

Recycling the Purpose of Old Drugs to Treat Ovarian Cancer

Nunes

Abreu

Bartosch

et al. 2020

IJMS

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“…Tang et al reported that profilin-2 (Pfn2) enhances Smad2/Smad3 expression, and high SMAD expression correlates with poor outcome of lung cancer patients [27]. In addition, several investigations have indicated the oncogenic roles of SMAD2 in pancreatic cancer, gastric cancer, and prostate cancer [28][29][30]. However, it is controversial for the functional roles of SMAD2 in cancer.…”

Section: Discussionmentioning

confidence: 99%

USP32 promotes tumorigenesis and chemoresistance in gastric carcinoma via upregulation of SMAD2

Dou¹,

Hu²,

Li³

et al. 2020

Int. J. Biol. Sci.

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USP32, a member of the ubiquitin-specific proteases family, has been implicated in the development of breast cancer and small lung cancer. However, its biological functions and clinical significance in gastric cancer (GC) remain unclear. In the present study, we reported that knockdown or depletion of USP32 significantly inhibited GC cell proliferation and migration in vitro and in vivo, indicating that USP32 functions as an oncogene in GC. Importantly, results from immunohistochemical staining in a tissue microarray revealed that USP32 was upregulated in GC tissues compared with paracancerous tissues. Further analyses showed that high expression of USP32 was closely related with high T-staging and poor outcomes of GC patients. Mechanistically, USP32 silencing caused a decrease in the expression of SMAD2, which resulted in the inhibitory effects of GC cells on growth, motility, and chemoresistance to cisplatin. Therefore, our findings strongly suggest the involvement of USP32 in GC progression and provide a potential target for future therapy of GC.

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“…The TGF-β/Smad pathway is an effective signaling pathway involved in the acceleration of oxidative stress, apoptosis and inflammation, and is therefore implicated in various diseases, including cardiac fibrosis ( 26 , 53 , 54 ). Among eight Smad family members (Smad1-8), Smad2/3 and Smad4 are the critical factors in the TGF-β pathway ( 55 ). The SUMOylation of Smad3 and Smad4 have been previously reported to inhibit TGF-β/Smad transcriptional activity ( 56 – 58 ).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of small ubiquitin‑like modifier 2 ameliorates high glucose‑induced reductions in cardiomyocyte proliferation via the transforming growth factor‑β/Smad pathway

Chun-hua

Shen

2018

Mol Med Report

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Hyperglycemia may induce diabetic cardiomyopathy (DC). In the current study, the mechanism underlying the alleviation of high glucose (HG)-induced impairments in the proliferation of H9c2 embryo cardiomyocyte proliferation by small ubiquitin-like modifier 2 (SUMO2) overexpression was investigated. H9c2 cell morphology was identified as classical long shuttle type by optical microscopy. The viability of HG-injured H9c2 cells was evaluated by a Cell Counting Kit-8 assay and the results indicated that viability was inhibited in a dose-dependent (5.6, 10, 20 and 30 mmol/l) and time-dependent (6, 12 and 24 h) manner. H9c2 cells treated with 20 mmol/l HG for 24 h were selected for subsequent experiments due to the extent of injury caused at a low density. Flow cytometry was conducted to confirm cell cycle arrest between G1/S phases and apoptosis promotion in HG-injured H9c2 cells, and the subsequent alleviating effect of SUMO2 overexpression on these HG-induced effects. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis were performed to detect mRNA and protein expression levels of cell cycle-and apoptosis-associated factors. The results indicated that the expression ofthe cell cycle-associated factors CyclinA2 and C-Myc was upregulated, and cyclin-dependent kinase inhibitor 1a was downregulated. The expression of the apoptosis-associated factor Bcl-2 was upregulated, while Bcl-2-associated X and caspase-3 expression was downregulated, by SUMO2 overexpression. Furthermore, the effect of SUMO2 overexpression on the transforming growth factor (TGF)-β/Smad pathway was also determined using RT-qPCR and western blot analysis. The results indicated the mRNA and protein levels of TGF-β1 and Smad3 in HG-injured H9c2 cells were significantly decreased following SUMO2 overexpression. Thus, the results demonstrated that overexpression of SUMO2 may alleviate H9c2 cardiomyocyte cell cycle arrest and apoptosis promotion induced by HG via regulation of cell cycle- and apoptosis-associated factors, as well as inhibition of the TGF-β/Smad pathway. These results may therefore provide a novel strategy for the protection of cardiomyocytes and may aid the diagnosis and prognosis of patients with DC.

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Itraconazole inhibits invasion and migration of pancreatic cancer cells by suppressing TGF-β/SMAD2/3 signaling

Cited by 16 publications

References 36 publications

Recycling the Purpose of Old Drugs to Treat Ovarian Cancer

Recycling the Purpose of Old Drugs to Treat Ovarian Cancer

USP32 promotes tumorigenesis and chemoresistance in gastric carcinoma via upregulation of SMAD2

Overexpression of small ubiquitin‑like modifier 2 ameliorates high glucose‑induced reductions in cardiomyocyte proliferation via the transforming growth factor‑β/Smad pathway

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