Pre-clinical evaluation of cinobufotalin as a potential anti-lung cancer agent

Sheng, Kai; Lu, Jiahuan; Hui, Pingping; Zhao, Hui

doi:10.1016/j.bbrc.2014.08.147

Cited by 50 publications

(42 citation statements)

References 32 publications

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“…Cinobufagin has been shown to enhance T-cell immune functions [38], enhance the secretion of IL-2 and IL-10 and increase the phagocytosis ability of macrophages [39]. This drug also reduces the incidence of infection in patients with cancer [40], raises the ratio of CD3 + /CD8 + and CD3 + /CD56 + cells and improves the cytotoxic activity and cell killing activity of cytokine-induced killer (CIK) cells [41]. Compared with the model group, the protein expression of CD3 + and CD8 + in the tumor and adjacent tissues of cinobufagin treated mice was significantly increased, suggesting that cinobufagin has a promoting effect on TILs.…”

Section: Discussionmentioning

confidence: 99%

Chinese herb cinobufagin-reduced cancer pain is associated with increased peripheral opioids by invaded CD3/4/8 lymphocytes

et al. 2016

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ObjectivesTo investigate the mechanism of cinobufagin-reduced cancer pain in mouse cancer pain model and in vitro cell co-culture system.MethodsFemale Kunming mice were randomly divided into 4 groups. One group of animals was set as normal control without any treatment. Other three groups of animals received H22 hepatoma cell inoculation in right hind paw. At day 9 after inoculation, mice in other three groups were injected intraperitoneally once a day for 8 days with the solvent, morphine or cinobufagin, respectively. The pain behavior was recorded daily. On the last day, all mice were sacrificed and xenograft tissues homogenate and plasma levels of β-endorphin (β-END), corticotropin-releasing factor (CRF) and interleukin-1β (IL-1β) were assessed by ELISA assay. Immunohistochemistry was performed to determine the expression of β-END, pro-opiomelanocortin (POMC) and the μ-opioid receptor (μ-OR) in the xenograft tissues. Immunofluorescence was used to localize lymphocytes with expression of CD3+, CD4+ and CD8+ in xenograft tumors and adjacent tissues. Mice splenic lymphocytes and H22 hepatoma carcinoma ascites cells were prepared for co-culture. β-END and CRF were detected in co-culture supernatants. The MTT assay and cytometry were used to assess cell proliferation. RT-PCR was conducted to determine the gene expression of POMC and Cathepsin L (CTSL). Chemotaxis was examined using a transwell-based migration assay.ResultsCompared to the model group, the thermal and mechanical pain thresholds were increased in mice after cinobufagin treatment. The expression of β-END and CRF in the plasma and tumor tissues of cinobufagin group were much higher than that of the model group mice, but the expression of IL-1β in the plasma and tumor tissues was much lower than that in the model group mice. Meanwhile, the expression of β-END, POMC and μ-OR proteins was significantly increased in the xenograft tissues from cinobufagin group. Lymphocyte population of CD3+, CD4+, CD8+ were also elevated in xenograft tumors and adjacent tissues. In the cell co-culture assays, the content of β-END in the supernatant was significantly increased by cinobufagin in a dose-dependent manner. Cinobufagin also largely increased the proliferation of immune cells and inhibited H22 hepatoma carcinoma cell proliferation in single or co-culture cell assays. Gene expression of POMC and CTSL in cinobufagin group was significantly up-regulated comparing to the control group. Finally, cinobufagin addition enhanced the migration of immune cells in transwell assay.ConclusionsCinobufagin-induced local analgesic effect might be associated with increased activity of POMC/β-END/μ-OR pathway released from invaded CD3/4/8 lymphocytes in cancer tissues.

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Section: Discussionmentioning

confidence: 99%

Chinese herb cinobufagin-reduced cancer pain is associated with increased peripheral opioids by invaded CD3/4/8 lymphocytes

et al. 2016

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“…Here, we showed that treatment with HepG2 cells with CC-223 (500 nM) also induced mitochondrial depolarization (JC-10 intensity increase, indicating mPTP opening [36,37,38,39]) (Fig 4A) and dramatic ROS production (Fig 4B). Thus, CC-223 apparently also disrupted mitochondrial functions in HCC cells.…”

Section: Resultsmentioning

confidence: 86%

“…Recent studies [36,37,38,39] including ours have demonstrated that a number of anti-cancer drugs would disrupt normal mitochondrial function, causing mitochondrial permeability transition pore (mPTP) opening, mitochondrial depolarization and reactive oxygen species (ROS) production, which mediate the subsequent cancer cell death. Here, we showed that treatment with HepG2 cells with CC-223 (500 nM) also induced mitochondrial depolarization (JC-10 intensity increase, indicating mPTP opening [36,37,38,39]) (Fig 4A) and dramatic ROS production (Fig 4B).…”

Section: Resultsmentioning

confidence: 99%

CC-223 blocks mTORC1/C2 activation and inhibits human hepatocellular carcinoma cells in vitro and in vivo

et al. 2017

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Hepatocellular carcinoma (HCC) is a leading cause of cancer-related human mortalities. Over-activation of mammalian target of rapamycin (mTOR) is important for HCC tumorigenesis and progression. The current study assessed the potential anti-HCC activity by a novel mTOR kinase inhibitor, CC-223. We demonstrate that CC-223, at nM concentrations, induced profound cytotoxic and anti-proliferative activities against established HCC cell lines (HepG2, KYN-2 and Huh-7) and primary human HCC cells. Meanwhile, CC-223 activated caspase-3/-9 and apoptosis in the above HCC cells. CC-223 concurrently blocked mTORC1 and mTORC2 activation, and its cytotoxicity against HCC cells was much more potent than the traditional mTORC1 inhibitors (RAD001 and rapamycin). Further studies demonstrated that CC-223 disrupted mitochondrial function, and induced mitochondrial permeability transition pore (mPTP) opening and reactive oxygen species (ROS) production. On the other hand, ROS scavengers and mPTP blockers (cyclosporin A or sanglifehrin A) largely attenuated CC-223-induced HepG2 cell apoptosis. In vivo studies showed that oral administration of CC-223 dramatically inhibited growth of HepG2 xenografts in severe combined immuno-deficient (SCID) mice. mTORC1/2 activation was also blocked in xenografts with CC-223 administration. Together, CC-223 simultaneously blocks mTORC1/2 and efficiently inhibits human HCC cells.

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“…The detailed protocol was described previously[24,25,26,27]. Briefly, following treatment, the mitochondria of HUVECs were isolated via the “Mitochondria Isolation Kit” (Sigma) [3].…”

Section: Methodsmentioning

confidence: 99%

AntagomiR-451 inhibits oxygen glucose deprivation (OGD)-induced HUVEC necrosis via activating AMPK signaling

et al. 2017

PLoS ONE

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Oxygen glucose deprivation (OGD) application in cultured human umbilical vein endothelial cells (HUVECs) mimics ischemic injuries. AntagomiR-451, the miroRNA-451 (“miR-451”) inhibitor, could activate pro-survival AMP-activated protein kinase (AMPK) signaling. In the current study, we showed that forced-expression of antagomiR-451 depleted miRNA-451 and significantly attenuated OGD-induced necrosis of HUVECs. Activation of AMPK was required for antagomiR-451-mediated pro-survival actions. AMPK inhibition, by AMPKα shRNA or dominant negative mutation, almost completely abolishedantagomiR-451-mediated HUVEC protection again OGD. Reversely, forced-activation of AMPK by exogenous expression of constructively-active AMPKα inhibited OGD-induced HUVEC necrosis. At the molecular level, antagomiR-451 expression in HUVECs inhibited OGD-induced programmed necrosis, the latter was evidenced by mitochondrial p53-cyclophilinD (Cyp-D) association, mitochondrial depolarization as well as reactive oxygen species (ROS) production and lactate dehydrogenase (LDH) breach. Together, we suggest that antagomiR-451 activates AMPK to inhibit OGD-induced programmed necrosis in HUVECs.

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Pre-clinical evaluation of cinobufotalin as a potential anti-lung cancer agent

Cited by 50 publications

References 32 publications

Chinese herb cinobufagin-reduced cancer pain is associated with increased peripheral opioids by invaded CD3/4/8 lymphocytes

Chinese herb cinobufagin-reduced cancer pain is associated with increased peripheral opioids by invaded CD3/4/8 lymphocytes

CC-223 blocks mTORC1/C2 activation and inhibits human hepatocellular carcinoma cells in vitro and in vivo

AntagomiR-451 inhibits oxygen glucose deprivation (OGD)-induced HUVEC necrosis via activating AMPK signaling

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