Inhibition of JAK2 Reverses Paclitaxel Resistance in Human Ovarian Cancer Cells

Xu, Yefang; Zhang, Jingjing; Wu, Jing; Zhong, Sheng

doi:10.1097/igc.0000000000000550

Cited by 13 publications

(9 citation statements)

References 21 publications

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“…Inhibition of STAT3 activity reverses chemoresistance and enhances chemotherapeutic drugs-induced apoptosis, accompanied by decreased level of pro-survival genes Bcl-xL, Bcl-2 and survivin 21,73,[75][76][77][78] . These results are in parallel with the findings that it increases toxicity of cisplatin or paclitaxel to ovarian cancer when treated with JAK2 or STAT3 inhibitor, such as AG490 79, 80 , WP1066 79,80 , Diindolylmethane 39 , SD-1029 45 , and SD-1008 46 . Moreover, a recent study reveals that STAT3 polymorphisms may function as an independent marker predicting a poor response to chemotherapy for patients with advanced serous EOC 82 .…”

Section: Induction Of Chemotherapy Resistancesupporting

confidence: 81%

“…Studies have suggested that AG490 exerts anti-tumor effects on several cancers, including acute lymphoblastic leukaemia 148 , head and neck squamous cell carcinoma 149 , ovarian cancer 150 and so on. Moreover, AG490 reverses paclitaxel resistance through decreasing the level of pSTAT3 and multidrug resistance protein 1 in ovarian cancer cells 150 . However, there is no clinical trial of AG490 in malignancies in spite of its anti-tumor efficacy in the preclinical studies.…”

Section: Indirect Inhibitors Of Stat3mentioning

confidence: 99%

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STAT3 signaling in ovarian cancer: a potential therapeutic target

Liang¹,

Chen²,

Chen³

et al. 2020

J. Cancer

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Accumulating evidence has shown that Signal Transducer and Activator of Transcription 3 (STAT3) is thought to be a promising target for cancer therapy as STAT3 is frequently overexpressed in a wide range of cancer cells as well as clinical specimens, promoting tumor progression. It is widely accepted that STAT3 regulates a variety of cellular processes, such as tumor cell growth, survival, invasion, cancer stem cell-like characteristic, angiogenesis and drug-resistance. In this review, we focus on the role of STAT3 in tumorigenesis in ovarian cancer and discuss the existing inhibitors of STAT3 signaling that can be promisingly developed as the strategies for ovarian cancer therapy.

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Section: Induction Of Chemotherapy Resistancesupporting

confidence: 81%

Section: Indirect Inhibitors Of Stat3mentioning

confidence: 99%

STAT3 signaling in ovarian cancer: a potential therapeutic target

Liang¹,

Chen²,

Chen³

et al. 2020

J. Cancer

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“…JAK/STAT pathway is a crucial signaling cascade known to be involved in the proliferation and survival of different cancer cells [43]. Silencing JAK2 has reported to enhance apoptosis in human gastric cancer cells [44], and delivering JAK2 siRNA has sensitized resistant ovarian cancer cells to paclitaxel [45]. Level of mRNA downregulation showed a similar trend to our observations with KSP silencing with the most efficient drop in mRNA levels for [R 5 K]W 5 /DOPE delivery system.…”

Section: Resultsmentioning

confidence: 99%

Amphiphilic Peptides for Efficient siRNA Delivery

et al. 2019

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A number of amphiphilic cyclic peptides—[FR]4, [WR]5, and [WK]5—containing hydrophobic and positively-charged amino acids were synthesized by Fmoc/tBu solid-phase peptide methods and evaluated for their efficiency in intracellular delivery of siRNA to triple-negative breast cancer cell lines, MDA-MB-231 and MDA-MB-468, in the presence and absence of 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE). Among the peptides, [WR]5, which contains alternate tryptophan (W) and arginine (R) residues, was found to be the most efficient in the delivery of siRNA by improving the delivery by more than 3-fold when compared to other synthesized cyclic peptides that were not efficient. The data also showed that co-formulation of [WR]5 with lipid DOPE significantly enhanced the efficiency of siRNA delivery by up to ~2-fold compared to peptide alone. Based on the data indicating the efficiency of [WR]5 in siRNA delivery, peptides containing arginine residues on the ring and tryptophan residues on the side chain, [R6K]W6 and [R5K]W5, were also evaluated, and demonstrated improved delivery of siRNA. The presence of DOPE again enhanced the siRNA delivery in most cases. [WR]5, [R5K]W5, and [R6K]W6 did not show any significant toxicity in MDA-MB-231, MDA-MB-468, and AU565 WT cells at N/P ratios of 20:1 or less, in the presence and absence of DOPE. Silencing of kinesin spindle protein (KSP) and Janus kinase 2 (JAK2) was evaluated in MDA-MB-231 cells in the presence of the peptides. The addition of DOPE significantly enhanced the silencing efficiency for all selected peptides. In conclusion, peptides containing tryptophan and arginine residues were found to enhance siRNA delivery and to generate silencing of targeted proteins in the presence of DOPE.

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“…Tyrphostin B42 (AG490) is an inhibitor of epidermal growth factor receptor (EGFR) by competing to binding sites with receptor tyrosine kinases (RTKs) (35). Tyrphostin B42 has been reported to have an inhibitory effect on the proliferation of many tumor cells through IL-6/JAK2/STAT3 signaling (22)(23)(24). A previous study revealed that in vitro AG-490 (60-100 µM) blocked the constitutive activation of Stat3 sm , and inhibited spontaneous as well as interleukin 2-induced growth of mycosis fungoides tumor cells (36).…”

Section: Discusssionmentioning

confidence: 99%

“…In the present study, we first investigated the activity of IL-6/JAK2/STAT3 signaling in patients with pancreatic cancer and in PCCs with (PANC-1-TSA) or without (PANC-1) TSA resistance. Secondly, tyrphostin B42 had been reported to possess inhibitory activity on the proliferation of various tumor cells (22,23), and to be associated with IL-6/JAK2/STAT3 signaling (24). Therefore, in the present study the effects of tyrphostin B42 on TSA-induced over-proliferation and resistance of PCCs were also evaluated.…”

Section: Introductionmentioning

confidence: 95%

Tyrphostin B42 attenuates trichostatin A-mediated resistance in pancreatic cancer cells by antagonizing IL-6/JAK2/STAT3 signaling

Zhang

Hong

et al. 2018

Oncol Rep

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Drug-resistance is the key reason for the ineffectiveness of chemotherapy in pancreatic cancer. Thus, it is very important to explore the molecular mechanisms of drug‑resistance and the methods of effective intervention. In the present study, we investigated the effect of tyrphostin B42, also called AG490, on histone deacetylase (HDAC) inhibitor trichostatin A (TSA)‑induced resistance in pancreatic cancer cells (PCCs). Evidence from phase contrast microscope revealed that TSA‑resistant cells (PANC‑1‑TSA) had higher proliferative activity than non‑resistant cells (PANC‑1). This over‑proliferative activity induced by TSA may be associated with abnormal activation of JAK2/STAT3 signaling, which can be strengthened by interleukin‑6 (IL‑6), a STAT3‑upstream inducer, resulting in enhanced expression of STAT3-downstream target genes including c‑Myc, c‑Src, HIF‑1α, and CCND1. In addition, increased expression of Bcl‑2 mRNA and decreased expression of Bax mRNA in PANC‑1‑TSA cells indicated that TSA induced the inhibition of mitochondrial-dependent apoptosis in PCCs. Tyrphostin B42 treatment evidently antagonized the activation of IL‑6/JAK2/STAT3 in a dose‑dependent manner. As a result, tyrphostin B42 inhibited the over‑proliferative activity of PANC‑1‑TSA cells, and downregulated the expression of IL‑6/JAK2/STAT3‑downstream target genes. Moreover, tyrphostin B42 induced the apoptosis of PCCs by regulating the expression of mitochondrial‑related genes. Therefore, these findings demonstrated that tyrphostin B42 attenuated TSA‑mediated resistance in PCCs by antagonizing the IL‑6/JAK2/STAT3 signaling.

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Inhibition of JAK2 Reverses Paclitaxel Resistance in Human Ovarian Cancer Cells

Abstract: Collectively, we conclude that the JAK2-STAT3 pathway promotes the development of paclitaxel resistance via upregulating the expression of prosurvival and antiapoptotic genes. Targeting this pathway may be effective in reversing resistance to chemotherapy in ovarian cancers.

Cited by 13 publications

References 21 publications

STAT3 signaling in ovarian cancer: a potential therapeutic target

STAT3 signaling in ovarian cancer: a potential therapeutic target

Amphiphilic Peptides for Efficient siRNA Delivery

Tyrphostin B42 attenuates trichostatin A-mediated resistance in pancreatic cancer cells by antagonizing IL-6/JAK2/STAT3 signaling

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