The novel JNK inhibitor AS602801 inhibits cancer stem cells <i>in vitro</i> and <i>in vivo</i>

Okada, Masashi; Kuramoto, Kenta; Takeda, Hiroyuki; Watarai, Hikaru; Sakaki, Hirotsugu; Seino, Shizuka; Seino, Manabu; Suzuki, Shuhei; Kitanaka, Chifumi

doi:10.18632/oncotarget.8395

Cited by 59 publications

(74 citation statements)

References 37 publications

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“…CC‐930 is being tested in idiopathic pulmonary fibrosis and high‐dose CC‐930 caused elevation of hepatic transaminases when used for long‐term treatment . AS602801 is being tested in endometriosis and demonstrated favorable safety and tolerability after 5 months of administration . Both diseases are benign, chronic inflammatory diseases, and the efficacy of the inhibitors has not been examined in malignant tumor patients; our results suggest that it is worth examining the safety and tolerability in those patients.…”

Section: Discussionmentioning

confidence: 89%

c‐Jun N‐terminal kinase in pancreatic tumor stroma augments tumor development in mice

et al. 2017

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Pancreatic ductal adenocarcinoma (PDAC) is a life‐threatening disease and there is an urgent need to develop improved therapeutic approaches. The role of c‐Jun N‐terminal kinase (JNK) in PDAC stroma is not well defined even though dense desmoplastic reactions are characteristic of PDAC histology. We aimed to explore the role of JNK in PDAC stroma in mice. We crossed Ptf1a Cre/+;Kras G12D/+ mice with JNK1 −/− mice to generate Ptf1a Cre/+ ;Kras G12D/+ ;JNK1 −/− (Kras;JNK1−/−) mice. Tumor weight was significantly lower in Kras;JNK1−/− mice than in Kras;JNK1+/− mice, whereas histopathological features were similar. We also transplanted a murine PDAC cell line (mPC) with intact JNK1 s.c. into WT and JNK1 −/− mice. Tumor diameters were significantly smaller in JNK1 −/− mice. Phosphorylated JNK (p‐JNK) was activated in α‐smooth muscle actin (SMA)‐positive cells in tumor stroma, and mPC‐conditioned medium activated p‐JNK in tumor‐associated fibroblasts (TAF) in vitro. Relative expression of Ccl20 was downregulated in stimulated TAF. Ccl20 is an important chemokine that promotes CD8+ T‐cell infiltration by recruitment of dendritic cells, and the number of CD8+ T cells was decreased in Kras;JNK1+/− mice compared with Kras;JNK1−/− mice. These results suggest that the cancer secretome decreases Ccl20 secretion from TAF by activation of JNK, and downregulation of Ccl20 secretion might be correlated with reduction of infiltrating CD8+ T cells. Therefore, we concluded that inhibition of activated JNK in pancreatic tumor stroma could be a potential therapeutic target to increase Ccl20 secretion from TAF and induce accumulation of CD8+ T cells, which would be expected to enhance antitumor immunity.

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Section: Discussionmentioning

confidence: 89%

c‐Jun N‐terminal kinase in pancreatic tumor stroma augments tumor development in mice

et al. 2017

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“…In the present study, we also found that the expression levels of the TFAM and c‐Myc proteins in GSCs were higher than those detected in isogenic differentiated GSCs. Moreover, studies by us and others previously demonstrated that the c‐Myc protein levels were elevated in CSCs including GSCs and that high c‐Myc expression and activity were implicated in the maintenance of CSC properties . Therefore, the c‐Myc/TFAM/complex III/complex IV axis in GSCs is a candidate for effective, safe and specific therapeutic targets.…”

Section: Discussionmentioning

confidence: 96%

“…Viable and dead cells were identified by their ability and inability to exclude vital dyes, respectively . Briefly, cells were treated with drugs as described and stained with 0.2% trypan blue for 1 min at room temperature (RT), and the number of viable and dead cells was determined using a haemocytometer.…”

Section: Methodsmentioning

confidence: 99%

Verteporfin inhibits oxidative phosphorylation and induces cell death specifically in glioma stem cells

et al. 2020

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Glioblastoma multiforme (GBM) is the most malignant primary brain tumour in adults. Since glioma stem cells (GSCs) are associated with therapeutic resistance as well as the initiation and recurrence in GBM, therapies targeting GSCs are considered to be effective for long-term survival in GBM. Several reports suggested that oxidative phosphorylation (OXPHOS) of cancer stem cells is important for their survival; however, the requirement of OXPHOS in GSCs remains unclear. Few effective and safe agents that target GSC mitochondria are available in clinical settings.In this study, we demonstrated that GSCs had high OXPHOS activity compared with isogenic differentiated GSCs and that GSC survival depended on their OXPHOS activity. Remarkably, we showed that complexes III and IV had broad therapeutic windows and that the expression levels of mitochondrial DNA-coded components of complexes III and IV were elevated in GSCs compared with differentiated GSCs. Moreover, our search of the Food and Drug Administration-approved drugs for those targeting GSC mitochondria revealed that verteporfin (Visudyne Ò ), a drug approved for macular degeneration, was a novel GSC-specific cytotoxic compound that reduced OXPHOS activity. Importantly, the cytotoxic effect of verteporfin was specific to GSCs without any toxicity to normal cells, and the IC 50 of approximately 200 nM was ten times less than its maximum blood concentration in humans. Overall, these findings indicated that high mitochondrial OXPHOS of GSCs is a potential GSC-specific vulnerability and that clinically available drugs, such as verteporfin, might become novel GSC-specific cytotoxic agents.

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“…[80] In another report, the JNK1 (c-Jun N-terminal kinase) inhibitor bentamapimod was shown to exhibit growth-inhibitory effects in CSCs derived from xenografts of human pancreatic, non-small cell lung and ovarian cancers, and from glioblastoma. [82] However, the mechanism of action leading to the apparent specificity for CSCs remains to be fully elucidated. Finally, repertaxin, a CXCR1 (interleukin 8 receptor) inhibitor, could target breast CSCs, and the same effect was observed with a CXCR1-specific antibody.…”

Section: Miscellaneousmentioning

confidence: 99%

Targeting Cancer Stem Cells with Small Molecules

Müller

Cañeque

Acevedo

et al. 2017

Israel Journal of Chemistry

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Cancers arise as a result of physiological imbalances and subsequent uncontrolled cell division. Cancer initiation requires a set of biochemical alterations, including some occurring at the genetic and epigenetic levels. Thus, tumors are heterogeneous in nature making it challenging to selectively target different cancer cells by means of small molecule intervention. The paradigm of cancer stem cells (CSCs) describes subpopulations of cells with high selfrenewal and tumor-seeding capacity. These cells, typically refractory to conventional therapies, can give rise to relapse after treatment. Combinatorial strategies, including drugs that selectively target this population of cells, have emerged in recent years. Here, we review how discovery-basedunbiased -screening approaches [1] have helped identify small molecules that specifically target CSCs. We also highlight biological pathways characteristic of CSCs that can potentially be selectively targeted in a hypothesis-driven manner by small molecules. We describe molecules that effectively target CSCs and emphasize what is known about their biological modes of action. The diversity and complexity of biochemical processes that CSCs may be addicted to, raises the question of how selective targeting of these pathways can be achieved. This challenge may be addressed by the continuing production of structurally complex and diverse small molecules using target and diversity-oriented synthesis approaches.[2]

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The novel JNK inhibitor AS602801 inhibits cancer stem cells in vitro and in vivo

Cited by 59 publications

References 37 publications

c‐Jun N‐terminal kinase in pancreatic tumor stroma augments tumor development in mice

c‐Jun N‐terminal kinase in pancreatic tumor stroma augments tumor development in mice

Verteporfin inhibits oxidative phosphorylation and induces cell death specifically in glioma stem cells

Targeting Cancer Stem Cells with Small Molecules

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