Conophylline suppresses hepatic stellate cells and attenuates thioacetamide‐induced liver fibrosis in rats

Kubo, Norio; Saito, Rie; Hamano, Kunihisa; Nagasawa, Mitsuru; Aoki, Fumiaki; Takei, Izumi; Umezawa, Kazuo; Kuwano, Hiroyuki; Kojima, Itaru

doi:10.1111/liv.12328

Cited by 21 publications

(22 citation statements)

References 37 publications

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“…We previously reported that CnP suppressed liver fibrosis induced by thioacetamide through the suppression of hepatic stellate cells . Similarly, in the present study, CnP suppressed the desmoplastic changes in tumors that consisted of pancreatic cancer cells and CAF in a mouse xenograft model.…”

Section: Discussionsupporting

confidence: 83%

“…We previously reported that CnP suppressed liver fibrosis induced by thioacetamide through the suppression of hepatic stellate cells. 10 Similarly, in the present study, CnP suppressed the desmo- cells was significantly higher than that of SUIT-2 cells alone. E, α-SMA-positive stained area of tumors consisting of SUIT-2 + hPSC5 cells was significantly higher than that of SUIT-2 cells alone.…”

Section: Discussionsupporting

confidence: 77%

“…The CnP used in this study was isolated and purified from the leaves of E. microphylla and Tabernaemontana divaricata, and prepared as described previously. 10,17 Briefly, pure CnP was dissolved in methanol and used in vitro; the final concentration of CnP was 0.05-1.0 μg/ mL, with a final methanol concentration of 0.1% (v/v). Crude CnP (containing 22 mg/g pure CnP) was used in vivo, diluted to 2 mg/mL in 0.5% (v/v) Tween-80 solution.…”

Section: Preparation Of Cnpmentioning

confidence: 99%

“…9 Recently, we reported that CnP suppressed thioacetamide-induced liver fibrosis through the inhibition of hepatic stellate cell activation. 10 Moreover, CnP was found to inhibit PSC and improve islet fibrosis in rat models of type-2 diabetes. 11 In these reports, CnP suppressed α-SMA expression, a marker of stellate cell activation, and type I collagen secretion of PSC and hepatic stellate cells.…”

Section: Introductionmentioning

confidence: 99%

“…Conophylline (CnP) is a vinca alkaloid extracted from the leaves of the tropical plant, Ervatamia microphylla , and has been shown to promote β‐cell differentiation in pancreatic precursor cells . Recently, we reported that CnP suppressed thioacetamide‐induced liver fibrosis through the inhibition of hepatic stellate cell activation . Moreover, CnP was found to inhibit PSC and improve islet fibrosis in rat models of type‐2 diabetes .…”

Section: Introductionmentioning

confidence: 99%

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Conophylline suppresses pancreatic cancer desmoplasia and cancer‐promoting cytokines produced by cancer‐associated fibroblasts

et al. 2018

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Despite recent advances in cancer treatment, pancreatic cancer is a highly malignant tumor type with a dismal prognosis and it is characterized by dense desmoplasia in the cancer tissue. Cancer‐associated fibroblasts (CAF) are responsible for this fibrotic stroma and promote cancer progression. We previously reported that a novel natural compound conophylline (CnP) extracted from the leaves of a tropical plant reduced liver and pancreatic fibrosis by suppression of stellate cells. However, there have been no studies to investigate the effects of CnP on CAF, which is the aim of this work. Here, we showed that CAF stimulated indicators of pancreatic cancer malignancy, such as proliferation, invasiveness, and chemoresistance. We also showed that CnP suppressed CAF activity and proliferation, and inhibited the stimulating effects of CAF on pancreatic cancer cells. Moreover, CnP strongly decreased the various cytokines involved in cancer progression, such as interleukin (IL)‐6, IL‐8, C‐C motif chemokine ligand 2 (CCL2), and C‐X‐C motif chemokine ligand 12 (CXCL12), secreted by CAF. In vivo, CAF promoted tumor proliferation and desmoplastic formation in a mouse xenograft model, CnP reduced desmoplasia of tumors composed of pancreatic cancer cells + CAF, and combination therapy of CnP with gemcitabine remarkably inhibited tumor proliferation. Our findings suggest that CnP is a promising therapeutic strategy of combination therapy with anticancer drugs to overcome refractory pancreatic cancers.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionsupporting

confidence: 77%

Section: Preparation Of Cnpmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Conophylline suppresses pancreatic cancer desmoplasia and cancer‐promoting cytokines produced by cancer‐associated fibroblasts

et al. 2018

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Conophylline Suppresses Angiotensin II-Induced Myocardial Fibrosis In Vitro via the BMP4/JNK Pathway

et al. 2021

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Therapeutic activity of plant-derived alkaloid conophylline on metabolic syndrome and neurodegenerative disease models

et al. 2017

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Increasing metabolic syndromes including type-2 diabetes mellitus, obesity, and steatohepatitis are serious problems in most countries in the world. Neurodegenerative diseases such as Alzheimer, Parkinson's, and Huntington's diseases are increasing in many countries. However, therapy for these diseases is not sufficient yet. Thus, effective chemotherapy for these diseases is being expected. Conophylline is an alkaloid isolated from the leaves of Ervatamia microphylla and related plants. It was found to induce beta-cell differentiation in the precursor pancreatic cells. Oral administration of this compound ameliorated type-2 diabetes mellitus model in mice and rats. Later, fibrosis of the pancreatic islets was found to be greatly reduced by conophylline in the pancreatic islets. It also inhibited chemically induced liver cirrhosis. Further study indicated that conophylline inhibited non-alcoholic steatohepatitis in the model mice. On the one hand, loss of autophagy often causes protein aggregation to give neural cell death. Conophylline was found to activate autophagy in cultured neural cells. Activation of autophagy ameliorated cellular models of Parkinson's and Huntington's diseases. Thus, conophylline is likely to be useful for the development of chemotherapy for metabolic and neurodegenerative diseases.

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Conophylline suppresses hepatic stellate cells and attenuates thioacetamide‐induced liver fibrosis in rats

Abstract: Conophylline suppresses HSC and induces apoptosis in vitro. CnP also attenuates formation of the liver fibrosis induced by TAA in vivo.

Cited by 21 publications

References 37 publications

Conophylline suppresses pancreatic cancer desmoplasia and cancer‐promoting cytokines produced by cancer‐associated fibroblasts

Conophylline suppresses pancreatic cancer desmoplasia and cancer‐promoting cytokines produced by cancer‐associated fibroblasts

Conophylline Suppresses Angiotensin II-Induced Myocardial Fibrosis In Vitro via the BMP4/JNK Pathway

Therapeutic activity of plant-derived alkaloid conophylline on metabolic syndrome and neurodegenerative disease models

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