The concerted actions of microRNA-29a and interferon-β modulate complete Freund's adjuvant-induced inflammatory pain by regulating the expression of type 1 interferon receptor, interferon-stimulated gene 15, and p-extracellular signal-regulated kinase

Article

作者: Liu, Chien-Cheng ; Chow, Lok-Hi ; Li, Yu-Yu ; Tan, Ping-Heng ; Yi-Kung Huang, Eagle ; Chu, Chin-Chen ; Hung, Kuo-Chuan

Background:

Previous research has shown that type 1 interferons (IFN), such as IFN-α and IFN-ß, possess antiviral and antinociception effects. Elevated levels of microRNA-29a (miR-29a) have been observed during inflammatory pain, and as miR-29a targets the type 1 IFN receptor (IFNR1), our study aimed to investigate the involvement of miR-29a, type 1 IFN, and IFNR1 in inflammatory pain.

Methods:

Inflammatory pain was induced in male rats using complete Freund's adjuvant (CFA). The changes in miR-29a, IFN-ß, and IFNR1 were measured on Days 2, 3, 5, 7, and 10 post-CFA injection and expression of IFNR1, phospho-ERK (phosphorylated extracellular signal-regulated kinase) (p-ERK), extracellular signal-regulated kinase (ERK), and IFN-stimulated gene 15 (ISG15) were measured in rats that received an miR-29a inhibitor or miR-29a mimic.

Results:

Our results demonstrated elevated miR-29a expression (CFA 3 days: mean difference [95% confidence interval, CI]: 0.860 [0.657-1.062]; CFA 5 days: mean difference [95% CI]: 1.120 [0.917-1.322], P<0.001, n=6) and decreased IFNR1 expression (CFA 3 days: mean difference [95% CI]: -0.300 [-0.470 to -0.130]; CFA 5 days: mean difference [95% CI]: -0.330 [-0.515 to -0.145], P=0.004, n=6) from Days 3-5 post-CFA induction, with IFN-ß expression showing a significant increase from Day 2 (F [3.30, 16.5]=34.3 for factor time, P≤0.01, n=6). Treatment with an miR-29a inhibitor alleviated CFA-induced mechanical allodynia and thermal hyperalgesia by Day 5 (P<0.001, n=9), concomitant with upregulation of IFNR1 and ISG15 expression, and downregulation of p-ERK (IFNR1; CFA 5 days + miR-29a inhibitor vs CFA 5 days; mean difference [95% CI]: 30.00 [20.31-39.69]; ISG15 conjugates; CFA 5 days + miR-29a inhibitor vs CFA 5 days, mean difference [95% CI]: 1.000 [0.9144-1.086]; free ISG15, mean difference [95% CI]: 2.402 [2.171-2.633]; p-ERK; CFA 5 days + miR-29a inhibitor vs CFA 5 days, mean difference [95% CI]: -32.00 [-34.10 to -29.90], P<0.001, n=9). Furthermore, in naïve rats, administration of an miR-29a mimic-induced mechanical allodynia, which was reversed by an ERK antagonist (P<0.001, n=6), associated with decreased IFNR1 and increased p-ERK expression (IFNR1; miR-29a mimic + dimethyl sulfoxide vs naïve; mean difference [95% CI]: -57.00 [-65.78 to -48.22]; miR-29a mimic + ASN007 vs naïve; mean difference [95% CI]: -60.00 [-71.00 to -49.00]. p-ERK; miR-29a mimic + dimethyl sulfoxide vs naïve, mean difference [95% CI]: 52.00 [47.01-56.99]; miR-29a mimic + ASN007 vs naïve, mean difference [95% CI]: 47.00 [42.51-51.49]; P<0.001, n=6).

Conclusions:

Inhibiting miR-29a expression attenuates inflammatory pain by modulating IFNR1, ISG15, and p-ERK expression, highlighting the interactive roles of miR-29a and IFN-ß in the regulation of inflammatory pain.

2022-04-01·Investigational new drugs3区 · 医学

ERK inhibitor ASN007 effectively overcomes acquired resistance to EGFR inhibitor in non‐small cell lung cancer

3区 · 医学

Article

作者: Kim, Jinchul ; Heo, Jae Yeong ; Ku, Bo Mi ; Sun, Jong-Mu ; Ahn, Jin Seok ; Ahn, Myung-Ju ; Park, Keunchil ; Lee, Se-Hoon

Summary:

The emergence of acquired resistance limits the long-term efficacy of EGFR tyrosine kinase inhibitors (EGFR TKIs). Thus, development of effective strategies to overcome resistance to EGFR TKI is urgently needed. Multiple mechanisms to reactivate ERK signaling have been successfully demonstrated in acquired resistance models. We found that in EGFR mutant non-small cell lung cancer (NSCLC) patients, acquired resistance to EGFR TKIs was accompanied by increased activation of ERK. Increased ERK activation was also found in in vitro models of acquired EGFR TKI resistance. ASN007 is a potent selective ERK1/2 inhibitor with promising antitumor activity in cancers with BRAF and RAS mutations. ASN007 treatment impeded tumor cell growth and the cell cycle in EGFR TKI-resistant cells. In addition, combination treatment with ASN007 and EGFR TKIs significantly decreased the survival of resistant cells, enhanced induction of apoptosis, and effectively inhibited the growth of erlotinib-resistant xenografts, providing the preclinical rationale for testing combinations of ASN007 and EGFR TKIs in EGFR-mutated NSCLC patients. This study emphasizes the importance of targeting ERK signaling in maintaining the long-term benefits of EGFR TKIs by overcoming acquired resistance.

2021-07-01·Cell reports. Medicine

ASN007 is a selective ERK1/2 inhibitor with preferential activity against RAS-and RAF-mutant tumors

Article

作者: Gupta, Sandeep ; de Stanchina, Elisa ; Seshan, Venkatraman ; Portelinha, Ana ; Thompson, Scott ; Asgari, Zahra ; Da Silva Ferreira, Mariana ; Younes, Anas ; Denis, Louis ; Smith, Roger A ; Knezevic, Andrea ; Reddy, Sanjeeva

Inhibition of the extracellular signal-regulated kinases ERK1 and ERK2 (ERK1/2) offers a promising therapeutic strategy in cancers harboring activated RAS/RAF/MEK/ERK signaling pathways. Here, we describe an orally bioavailable and selective ERK1/2 inhibitor, ASN007, currently in clinical development for the treatment of cancer. In preclinical studies, ASN007 shows strong antiproliferative activity in tumors harboring mutations in BRAF and RAS (KRAS, NRAS, and HRAS). ASN007 demonstrates activity in a BRAF^V600E mutant melanoma tumor model that is resistant to BRAF and MEK inhibitors. The PI3K inhibitor copanlisib enhances the antiproliferative activity of ASN007 both in vitro and in vivo due to dual inhibition of RAS/MAPK and PI3K survival pathways. Our data provide a rationale for evaluating ASN007 in RAS/RAF-driven tumors as well as a mechanistic basis for combining ASN007 with PI3K inhibitors.

100 项与 ASN007(奥全生物) 相关的药物交易

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