Synergistic growth inhibition in HL-60 cells by the combination of acyclic retinoid and vitamin K2

Kitagawa, Junichi; Hara, Takeshi; Tsurumi, Hisashi; Ninomiya, Soranobu; Ogawa, Kosuke; Adachi, Seiji; Kanemura, Nobuhiro; Kasahara, Senji; Shimizu, Masahito; Moriwaki, Hisataka

doi:10.1007/s00432-010-0938-0

Cited by 11 publications

(12 citation statements)

References 29 publications

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“…Stained cells were analyzed within 1 hour. Annexin V-FITC-positive and PI-negative cells were counted as apoptotic cells as described previously (29).…”

Section: Apoptosis Assaysmentioning

confidence: 99%

Possible Role of Visfatin in Hepatoma Progression and the Effects of Branched-Chain Amino Acids on Visfatin-Induced Proliferation in Human Hepatoma Cells

Ninomiya

Shimizu

Imai

et al. 2011

Cancer Prevention Research

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Obesity and related metabolic abnormalities, including adipocytokine dysbalance, are risk factors for hepatocellular carcinoma (HCC). Visfatin, an adipocytokine that is highly expressed in visceral fat, is suggested to play a role in the progression of human malignancies. Branched-chain amino acids (BCAA) reduce the incidence of HCC in obese patients with liver cirrhosis and prevent obesity-related liver carcinogenesis in mice. In this study, we investigated the possible role of visfatin on HCC progression and the effects of BCAA on visfatin-induced proliferation of HCC cells. In patients with HCCs, serum visfatin levels were significantly correlated with stage progression and tumor enlargement. Visfatin preferentially stimulated the proliferation of HepG2, Hep3B, and HuH7 human HCC cells compared with Hc normal hepatocytes. Visfatin phosphorylated extracellular signal-regulated kinase (ERK), Akt, and GSK-3b proteins in HepG2 cells. LY294002 [a phosphoinositide-3-kinase (PI3K) inhibitor], PD98059 [a MAP/ERK 1 kinase (MEK1) inhibitor], CHIR99021 (a GSK-3b inhibitor), and BCAA significantly inhibited visfatin-induced proliferation in HepG2 cells. BCAA also inhibited phosphorylation of GSK-3b, increased cellular levels of p21 CIP1 , caused cell-cycle arrest in G 0 /G 1 phase, and induced apoptosis in HCC cells in the presence of visfatin. These findings suggest that visfatin plays a critical role in the proliferation of HCC cells and may be associated with the progression of this malignancy. In addition, BCAA might inhibit obesity-related liver carcinogenesis by targeting and, possibly, by overcoming the stimulatory effects of visfatin.

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“…Stained cells were analyzed within 1 hour. Annexin V-FITC-positive and PI-negative cells were counted as apoptotic cells as described previously (29).…”

Section: Apoptosis Assaysmentioning

confidence: 99%

Possible Role of Visfatin in Hepatoma Progression and the Effects of Branched-Chain Amino Acids on Visfatin-Induced Proliferation in Human Hepatoma Cells

Ninomiya

Shimizu

Imai

et al. 2011

Cancer Prevention Research

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“…[75] Combined treatment with ACR plus valproic acid, a histone deacetylase inhibitor, also acts synergistically to induce apoptosis and G 0 –G 1 cell cycle arrest in HCC cells by inhibiting phosphorylation of RXRα, ERK, Akt, and glycogen synthase kinase-3β proteins. [53] In addition to HCC, in both human pancreatic cancer and leukemia cells,[6676] the combination of ACR plus gemcitabine or vitamin K 2 synergistically inhibits cell growth and induces apoptosis by inhibiting Ras activation and RXRα phosphorylation. Moreover, induction of nuclear receptors that dimerize with RXR, such as RAR and PPAR,[7778] and recruitment of their ligands also exert synergistic growth inhibition in cancer cells when combined with ACR.…”

Section: Introductionmentioning

confidence: 99%

Acyclic retinoid in chemoprevention of hepatocellular carcinoma: Targeting phosphorylated retinoid X receptor-α for prevention of liver carcinogenesis

Shimizu¹,

Shirakami²,

Imai³

et al. 2012

J Carcinog

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One of the key features of hepatocellular carcinoma (HCC) is the high rate of intrahepatic recurrence that correlates with poor prognosis. Therefore, in order to improve the clinical outcome for patients with HCC, development of a chemopreventive agent that can decrease or delay the incidence of recurrence is a critical issue for urgent investigation. Acyclic retinoid (ACR), a synthetic retinoid, successfully improves HCC patient survival by preventing recurrence and the formation of secondary tumors. A malfunction of the retinoid X receptor-α (RXRα) due to phosphorylation by the Ras-MAPK signaling pathway plays a critical role in liver carcinogenesis, and ACR exerts chemopreventive effects on HCC development by inhibiting RXRα phosphorylation. Here, we review the relationship between retinoid signaling abnormalities and liver disease, the mechanisms of how RXRα phosphorylation contributes to liver carcinogenesis, and the detailed effects of ACR on preventing HCC development, especially based on the results of our basic and clinical research. We also outline the concept of “clonal deletion and inhibition” therapy, which is defined as the removal and inhibition of latent malignant clones from the liver before they expand into clinically detectable HCC, because ACR prevents the development of HCC by implementing this concept. Looking toward the future, we discuss “combination chemoprevention” using ACR as a key drug since it can generate a synergistic effect, and may thus be an effective new strategy for the prevention of HCC.

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“…Furthermore, loss-of-function experiments using chemical inhibitors indicated that the growth-suppression effect of VK2 derivatives was mediated by caspase/transglutaminase-related signaling pathways, which are underlie the cancer-selective cell death induced by ACR in HCC cells (15). Indeed, synergistic growth inhibition by ACR and VK2 in combination has been reported in the human promyelocytic cell line HL60 (28) and HCC cell line Huh7 (29) by virtue of sharing a similar side chain structure. However, the IC50 values of VK2 derivatives are more than 20 mm (Fig.…”

Section: Discussionmentioning

confidence: 99%

Carboxylic Derivatives of Vitamin K2 Inhibit Hepatocellular Carcinoma Cell Growth through Caspase/Transglutaminase-Related Signaling Pathways

Qin

Fujii

Shimizu

et al. 2015

J Nutr Sci Vitaminol

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Summary Chemoprevention of hepatocellular carcinoma (HCC) is one of the most challenging aspects of medical research. Vitamin K2 (VK2) has been suggested for its chemopreventive role in treatment of HCC, while inconsistent results in clinical trials have been reported. The present study was initiated to add to our insight into the anti-HCC cell proliferative effect of VK2 and its derivatives from a viewpoint of chemical structure. No significant effect was observed with original VK2, while VK2 derivatives bearing both isoprene units and a carboxyl-terminated side chain dose-dependently inhibited the growth of HCC cells without affecting normal liver cells. Loss-of-function analyses revealed that the anti-HCC cell activity by the VK2 derivatives was not mediated by a VK2 binding protein Bcl-2 homologous antagonist/killer (Bak) but rather associated with caspase/transglutaminase-related signaling pathways. Further studies on the carboxylic derivatives of VK2 bearing isoprene structural units introduced in this study might shed new light on the systemic treatment and prevention of HCC.

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Synergistic growth inhibition in HL-60 cells by the combination of acyclic retinoid and vitamin K2

Abstract: The synergistic effects of ACR and VK(2) on HL-60 cells may provide a novel strategy for treating leukemia.

Cited by 11 publications

References 29 publications

Possible Role of Visfatin in Hepatoma Progression and the Effects of Branched-Chain Amino Acids on Visfatin-Induced Proliferation in Human Hepatoma Cells

Possible Role of Visfatin in Hepatoma Progression and the Effects of Branched-Chain Amino Acids on Visfatin-Induced Proliferation in Human Hepatoma Cells

Acyclic retinoid in chemoprevention of hepatocellular carcinoma: Targeting phosphorylated retinoid X receptor-α for prevention of liver carcinogenesis

Carboxylic Derivatives of Vitamin K2 Inhibit Hepatocellular Carcinoma Cell Growth through Caspase/Transglutaminase-Related Signaling Pathways

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