Anticancer effect of resibufogenin on gastric carcinoma cells through the phosphoinositide 3‑kinase/protein kinase�B/glycogen synthase kinase 3β signaling pathway

Lü, Zhen; Xu, Aman; Yuan, Xiao; Chen, Kaiwei; Wang, Likun; Guo, Tao

doi:10.3892/ol.2018.8979

Cited by 10 publications

(13 citation statements)

References 27 publications

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“…RB has recently been identified as a potential anticancer agent for cancer treatment (Han et al, 2018; Li, Jiang, et al, 2019; Lu et al, 2018). For example, RB inhibited the development of ovarian cancer (Li, Jiang, et al, 2019), gastric cancer (Lu et al, 2018), and CRC (Han et al, 2018). In this study, we found that RB inhibited CRC cell proliferation and promoted cell death in a time‐ and dose‐dependent manner.…”

Section: Discussionmentioning

confidence: 99%

“…Hence, there is an urgent need to find new drugs for CRC treatment. RB has recently been identified as a potential anticancer agent for cancer treatment (Han et al, 2018;Li, Jiang, et al, 2019;Lu et al, 2018). For example, RB inhibited the development of ovarian cancer (Li, Jiang, et al, 2019), gastric cancer (Lu et al, 2018), and CRC (Han et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…Resibufogenin (RB) is extracted from the dried skin secretions of the Asiatic toad ( Bufo gargarizans ). It has been used as an anticancer drug for ovarian cancer (Li, Jiang, et al, 2019), gastric cancer (Lu et al, 2018) and CRC (Han et al, 2018). RB has been shown to inhibit CRC progression by triggering RIP3‐mediated necroptosis (Han et al, 2018), suggesting that RB could serve as a novel drug for CRC treatment in clinic, but the detailed molecular mechanisms are still not fully delineated.…”

Section: Introductionmentioning

confidence: 99%

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RETRACTED: Resibufogenin inhibited colorectal cancer cell growth and tumorigenesis through triggering ferroptosis and ROS production mediated by GPX4 inactivation

Shen

Wen-hai

Bai

et al. 2020

The Anatomical Record

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Resibufogenin (RB) has been used for cancer treatment, but the underlying mechanisms are still unclear. This study aimed to investigate the effects of RB treatment on colorectal cancer (CRC) cells, and to determine the underlying mechanisms. The cell counting kit‐8 assay was used to determine cell viability. Cell morphology was observed under light microscopy, and terminal deoxynucleotidyl transferase‐mediated dUTP nick‐end labeling assay was employed to detect cell apoptosis. Intracellular ferrous iron (Fe2+), malondialdehyde (MDA), glutathione (GSH), and reactive oxygen species levels were detected by using commercial iron assay kit, MDA assay kit, GSH assay kit, and 2,7‐dichlorodihydrofluorescein diacetate probes, respectively. The protein expressions were determined by Western blot and immunohistochemistry. RB inhibited cell viability in the CRC cell lines (HT29 and SW480) in a dose‐ and time‐dependent manner, and caused cytotoxicity to the normal colonic epithelial cell line (NCM460) at high dose. Similarly, RB induced morphological changes in CRC cells from normal to round shape, and promoted cell death. Of note, RB triggered oxidative stress and ferroptotic cell death in CRC cells, and only ferroptosis inhibitors (deferoxamine and ferrostatin‐1), instead of inhibitors for other types of cell death (apoptosis, autophagy, and necroptosis), reversed the inhibitory effects of RB on CRC cell proliferation. Furthermore, glutathione peroxidase 4 (GPX4) was inactivated by RB treatment, and overexpression of GPX4 alleviated RB‐induced oxidative cell death in CRC cells. Consistently, the in vivo experiments validated that RB also triggered oxidative stress, and inhibited CRC cells growth and tumorigenicity in mice models. RB can inhibit CRC cells growth and tumorigenesis by triggering ferroptotic cell death in a GPX4 inactivation‐dependent manner.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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RETRACTED: Resibufogenin inhibited colorectal cancer cell growth and tumorigenesis through triggering ferroptosis and ROS production mediated by GPX4 inactivation

Shen

Wen-hai

Bai

et al. 2020

The Anatomical Record

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“…For example, RB has been demonstrated to suppress colorectal cancer cell proliferation and metastasis by promoting necroptosis (Han et al, 2018). In gastric cancer, RB has been shown to inhibit cell proliferation and induce apoptosis by activating the PI3K/AKT/GSK3β signaling pathway (Lu et al, 2018). Consistent with previous studies, our results demonstrated that RB was able to inhibit cell proliferation and invasion in a dose‐dependent manner in vitro.…”

Section: Discussionmentioning

confidence: 99%

RETRACTED: Resibufogenin suppresses growth and metastasis through inducing caspase‐1‐dependent pyroptosis via ROS‐mediated NF‐κB suppression in non‐small cell lung cancer

Yin

Liu

et al. 2020

The Anatomical Record

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The purpose of this study is to explore the antitumor properties of resibufogenin (RB) in non‐small cell lung cancer (NSCLC) and elucidate its underlying mechanism. A549 and H520 cells were treated with various concentrations of RB with or without NLRP3 inhibitor (MCC950), caspase‐1 inhibitor (VX765), or N‐acetyl‐l‐cysteine (an ROS scavenger). Cell counting kit‐8 and colony formation assays were conducted to determine cell viability. Cell invasion was detected by using the transwell assay. The release of lactate dehydrogenase (LDH) was determined by the LDH detection assay. The protein expression levels of related genes were measured by western blotting and immunohistochemistry. The reactive oxygen species (ROS) level was detected by using a 2,7‐dichlorodihydrofluorescein diacetate ROS Assay Kit. The in vivo effects of RB were evaluated in a xenograft mouse model. RB treatment reduced cell viability and invasion in a dose‐dependent manner. Furthermore, RB also enhanced pyroptosis levels in A549 and H520 cells, as indicated by the increased release of LDH and pyroptosis‐related proteins. Interestingly, we also found that the antiproliferative and antimetastatic effects of RB were alleviated by the blockade of pyroptosis using NLRP3 inhibitor MCC950. Further study demonstrated that RB induced pyroptosis in a caspase‐1‐dependent manner, as evidenced by the finding that VX765 effectively reversed the effects of RB on A549 and H520 cells. We also found that RB could trigger caspase‐1‐dependent pyroptosis through ROS‐mediated NF‐κB suppression. In summary, our findings provide a potential antitumor agent and a novel insight into the mechanism of RB treatment of NSCLC.

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“…Protein concentrations were determined by DC protein assay reagent (Bio-Rad) and extracts resolved by SDS/PAGE, then transferred to PVDF membranes (Bio-Rad). Membranes were blocked for 2 h at room temperature in 0.1% TBS-Tween-20 containing 5% non-fat dried milk, washed, and then incubated with the following specific primary antibodies; anti-phospho-Akt (Ser473, #4060 from Cell Signaling Technology, 1:1000 dilution) (Lu et al, 2018), anti-total-Akt (#9272, 1:1000 dilution) (Li et al, 2018), anti-phospho-IGF-I Receptor-β (Tyr1135/1136)/Insulin Receptor-β (Tyr1150/1151) (#3024, 1:500 dilution) (De Filippis et al, 2018), anti-total-IGF1Rβ (sc-713# from Santa Cruz Biotechnology Inc., Dallas, Texas, 1:200 dilution) (Pagesy et al, 2016), anti-phospho-p44/42 ERK1/2 (Thr202/Tyr204, #9101, 1:2000 dilution) (Go et al, 2018), anti-total ERK1/2 (#4695, 1:3000 dilution) (Meng et al, 2018); Anti-Actin (sc-1616 from Santa Cruz Biotechnology, 1:1000 dilution) (Perić et al, 2017); and anti-CgA (HPA017369, Sigma-Aldrich, 1:500 dilution) (Marbiah et al, 2014). After washing, membranes were incubated with HRP-conjugated secondary antibodies (Santa Cruz Biotechnology) and proteins visualized using a Super Signal Chemiluminescence Assay kit (Pierce, Grand Island, NY).…”

Section: Methodsmentioning

confidence: 99%

Chromogranin A regulates neuroblastoma proliferation and phenotype

Zhang

Babayan

et al. 2019

Biology Open

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Neuroblastoma is a commonly encountered solid tumor in early childhood with high neuroplasticity, and differentiation therapy is hypothesized to lead to tumor mass shrinkage and/or symptom relief. CgA is a tissue specific protein restricted to the diffuse neuroendocrine system, and widely expressed in neuroblastomas. Using knockdown and knockout approaches to deplete CgA levels, we demonstrated that CgA loss inhibits SH-SY5Y cell proliferation and leads to a morphological shift with increased expression of Schwann and extracellular matrix specific molecules, and suppression of chromaffin features. We further confirmed the effects of CgA in a series of neuroblastoma cells with [BE(2)-M17 and IMR-32] and without (SK-N-SH) N-Myc amplification. We demonstrated that CgA depletion reduced IGF-II and IGFBP-2 expression, increased IGFBP-3 levels, and suppresses IGF downstream signaling as evidenced by reduced AKT/ERK pathway activation. This was further supported by an increased anti-proliferative effect of the ERK inhibitor in the CgA depleted cells. In an in vivo xenograft neuroblastoma model, CgA knockdown led to increased S-phenotypic marker expression at both protein and mRNA levels. Together these results suggest that CgA maintains IGF secretion and intracellular signaling to regulate proliferation and differentiation in neuroblastomas.

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Anticancer effect of resibufogenin on gastric carcinoma cells through the phosphoinositide 3‑kinase/protein kinase�B/glycogen synthase kinase 3β signaling pathway

Cited by 10 publications

References 27 publications

RETRACTED: Resibufogenin inhibited colorectal cancer cell growth and tumorigenesis through triggering ferroptosis and ROS production mediated by GPX4 inactivation

RETRACTED: Resibufogenin inhibited colorectal cancer cell growth and tumorigenesis through triggering ferroptosis and ROS production mediated by GPX4 inactivation

RETRACTED: Resibufogenin suppresses growth and metastasis through inducing caspase‐1‐dependent pyroptosis via ROS‐mediated NF‐κB suppression in non‐small cell lung cancer

Chromogranin A regulates neuroblastoma proliferation and phenotype

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