Inhibition of invasion and migration of salivary gland adenocarcinoma cells by 5′‐nitro‐indirubinoxime (5′‐NIO)

Yoon, Ji-Hye; Kim, Soo‐A; Kim, Jae-Il; Park, Jong‐Hwan; Ahn, Sang‐Gun; Yoon, Jung‐Hoon

doi:10.1002/hed.21230

Cited by 5 publications

(4 citation statements)

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“…The current study first evaluated the anti-migration/invasion effects of Indox on a spontaneous PDAC mouse model and the underlying mechanisms using the mice-derived cell lines. Previous reports demonstrated that indirubin derivatives inhibited the migration and invasion activities in other cancer and endothelial cells [26], [27], [28], [29], [30], [31], [32]. Indox blocked the invasion of the human myeloid cell line KBM-5 by the down-regulation of MMP-9 [26].…”

Section: Discussionmentioning

confidence: 93%

“…Indox blocked the invasion of the human myeloid cell line KBM-5 by the down-regulation of MMP-9 [26]. In another study, 5-nitroindirubin 3′-oxime (5NO 2 Indox) inhibited the migration and invasion of salivary gland ductal adenocarcinoma by suppression of beta1 integrin and MMP-2 and -9 [27]. Furthermore, 6-bromoindirubin 3′-oxime (6BrIndox) also blocked the migration and invasion potential of colorectal and invasive urinary bladder carcinomas, accompanied with down-regulation of MMP-2 and -9 [28], [29].…”

Section: Discussionmentioning

confidence: 98%

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Indirubin 3′-Oxime Inhibits Migration, Invasion, and Metastasis in Mice Bearing Spontaneously Occurring Pancreatic Cancer via Blocking the RAF/ERK, AKT, and SAPK/JNK Pathways

Ichimaru

Sano

Kajiwara

et al. 2019

Translational Oncology

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BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with high invasive and metastatic potential. We generated a spontaneous PDAC mouse model and examined the therapeutic potential of indirubin 3′-oxime (Indox) against PDAC bearing mouse in vivo. METHODS: Randomized 3-month-old LSL-KrasG12D/+;Trp53flox/+;Pdx-1-cre (KPCflox) mice were intraperitoneally injected with 40 mg/kg Indox (n = 9) or a vehicle (n = 10) twice a week. At the end point, tumor status including proliferation, direct invasion, and distant metastasis was analyzed histopathologically. The inhibitory potentials of Indox for proliferation, migration/invasion, and the phosphorylation of target molecules were determined in KPCflox-derived PDAC cells in vitro. RESULTS: Prolonged survival by Indox via intraperitoneal administration was observed in the KPCflox mice. Indox inhibited tumor proliferation accompanied with low levels of nuclear phosphorylated cyclin-dependent kinase (p-CDK) and cyclin B1 in vivo. Furthermore, Indox inhibited the migration/invasive activities of PDAC via down-regulation of matrix metalloproteinase (MMP)-9 in vitro and in vivo. Antibody array and immunoblotting analysis revealed that Indox inhibited the phosphorylation of multiple molecules, including key upstream proteins of MMP-9 in RAF/extracellular signal-regulated kinase (ERK), AKT, and stress-activated protein kinase/c-Jun-N-terminal kinase (SAPK/JNK) pathways. CONCLUSION: Indox inhibited the proliferative, invasive, and metastatic potentials of PDAC in vitro and in vivo. Therefore, Indox could a therapeutic candidate for treating spontaneously occurring PDAC via blocking the RAF/ERK, AKT and SAPK/JNK pathways.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 98%

Indirubin 3′-Oxime Inhibits Migration, Invasion, and Metastasis in Mice Bearing Spontaneously Occurring Pancreatic Cancer via Blocking the RAF/ERK, AKT, and SAPK/JNK Pathways

Ichimaru

Sano

Kajiwara

et al. 2019

Translational Oncology

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“…MMP activity has been related with tumor cell proliferation and migration (26). Proliferation is an important factor in metastatic progression.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of discoidin domain receptor 2 in A375 human melanoma cells reduces its experimental liver metastasis ability

Badiola

Villacé²,

Basaldua³

et al. 2011

Oncol Rep

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Abstract. Discoidin domain receptors (DDr1 and DDr2) are tyrosine kinase receptors for fibrillar collagen implicated in postnatal development, tissue repair, and primary and metastatic cancer progression. While DDR1 has been described in tumor cells, DDR2 has been localized in the tumor stroma, but its presence in the tumor cells remains unknown. The aim of this study was to elucidate the role of DDR2 signaling in tumor cells during hepatic metastasis progression. DDR2 expression and phosphorylation in cultured human A375 melanoma cells was documented by Western blot analysis. A375 cells were stably transfected with a small interfering RNA (siRNA) against DDR2 and two clones were selected: A375R2-70 and A375R2-40, with 70 and 40% of the DDR2 protein expression respectively, compared to mock-transfected cells (A375R2-100). Development of experimental liver metastasis by intrasplenic inoculation of A375R2-70 and A37R2-40 clones was reduced by 60 and 75%, respectively, measured as tumor volume, compared to livers injected with A375R2-100 cells. Accordingly, A375R2-70 and A37R2-40 clones showed reduced in vitro gelatinase activity and JNK phosphorylation, compared to mock transfected cells, with maximal inhibition in A375R2-40. Additionally, A375 melanoma, SK-HEP hepatoma and HT-29 colon carcinoma human cell lines transiently transfected with siRNA against DDR2 also showed reduced proliferation and migration rates compared to mock-transfected ones. In conclusion, DDR2 promotes A375 melanoma metastasis to the liver and the underlying mechanism implicates regulation of metalloproteinase release, cell growth and chemotactic invasion of the host tissue.

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“…A number of recent studies have identified numerous alternative modes for the cytotoxic and antiangiogenic actions displayed by indirubin and some of its derivatives. Other actions of the indirubins include suppression of the VEGFR-2-mediated JAK/STAT3 signalling pathway by indirubin (13) [85]; inhibition of alternative kinases such as Fms-like tyrosine kinase 3 by indirubin-3'-oxime (14a) and its 6-bromo analogue [86]; and inhibition of polo-like kinase 1 [87] as well as downregulation of Notch-1 and inhibition of Integrin β1/FAK/Akt signalling by 5-nitroindirubin-3'-oxime (14b) [86,[88][89][90].…”

Section: Indirubin Is the Active Component In The Traditional Chinesementioning

confidence: 99%

Recent Highlights in the Development of Isatin-Based Anticancer Agents

Vine¹,

Matesic²,

Locke³

et al. 2013

Advances in Anticancer Agents in Medicinal Chemistry

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Isatin (1H-indole-2,3-dione) and its derivatives are responsible for a broad spectrum of biological activities. Among these the cytotoxic and antineoplastic properties have been the most widely reported. The synthetic versatility of the isatin, due to its privileged scaffold, has led to the generation of a large number of structurally diverse derivatives which include analogues derived from either mono-, di-, and trisubstitution of the aryl ring A, and/or those obtained by derivatisation of the isatin nitrogen and C2/C3 carbonyl moieties. These compounds inhibit cancer cell proliferation and tumour growth via interaction with a variety of intracellular targets such as DNA, telomerase, tubulin, P-glycoprotein, protein kinases and phosphatases. Herein we review recent highlights in the development of isatin-based compounds as anticancer agents with a particular focus on the cytotoxicity and structure activity relationships. Abstract:Isatin (1H-indole-2,3-dione) and its derivatives are responsible for a broad spectrum of biological activities. Among these the cytotoxic and antineoplastic properties have been the most widely reported. The synthetic versatility of the isatin, due to its privileged scaffold, has led to the generation of a large number of structurally diverse derivatives which include analogues derived from either mono-, di-, and tri-substitution of the aryl ring A, and/or those obtained by derivatisation of the isatin nitrogen and C2/C3 carbonyl moieties. These compounds inhibit cancer cell proliferation and tumour growth via interaction with a variety of intracellular targets such as DNA, telomerase, tubulin, Pglycoprotein, protein kinases and phosphatases. Herein we review recent highlights in the development of isatin-based compounds as anticancer agents with a particular focus on the cytotoxicity and structure activity relationships.

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Inhibition of invasion and migration of salivary gland adenocarcinoma cells by 5′‐nitro‐indirubinoxime (5′‐NIO)

Abstract: Taken together, these results suggest that 5'-NIO, even at low concentrations, may effectively inhibit the invasion and migration of SGT cells by suppressing beta1 integrin-mediated signaling.

Cited by 5 publications

References 44 publications

Indirubin 3′-Oxime Inhibits Migration, Invasion, and Metastasis in Mice Bearing Spontaneously Occurring Pancreatic Cancer via Blocking the RAF/ERK, AKT, and SAPK/JNK Pathways

Indirubin 3′-Oxime Inhibits Migration, Invasion, and Metastasis in Mice Bearing Spontaneously Occurring Pancreatic Cancer via Blocking the RAF/ERK, AKT, and SAPK/JNK Pathways

Downregulation of discoidin domain receptor 2 in A375 human melanoma cells reduces its experimental liver metastasis ability

Recent Highlights in the Development of Isatin-Based Anticancer Agents

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