Rhein triggers apoptosis via induction of endoplasmic reticulum stress, caspase-4 and intracellular calcium in primary human hepatic HL-7702 cells

KoraMagazi, Arouna; Wang, Dandan; Yousef, Bashir A.; Guerram, Mounia; Feng, Yu

doi:10.1016/j.bbrc.2016.03.084

Cited by 21 publications

(13 citation statements)

References 29 publications

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“…Inhibition of Na + /K + -ATPase pump by cardiac glycosides results in an increase in intracellular Ca ++ level which increases contractility of the heart [ 17 , 18 ]. Other studies reported that an increase in intracellular Ca ++ level leads to induction of ROS generation and apoptosis [ 32 , 33 ]. Although the ability of cardiac glycosides to increase intracellular Ca ++ level by inhibiting Na + /K + -ATPase pump has initially been suggested the primary event for their anticancer activity, however, this hypothesis has not always been verified.…”

Section: Discussionmentioning

confidence: 99%

Proscillaridin A Promotes Oxidative Stress and ER Stress, Inhibits STAT3 Activation, and Induces Apoptosis in A549 Lung Adenocarcinoma Cells

Maryam

Mehmood

Yan

et al. 2018

Oxidative Medicine and Cellular Longevity

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Cardiac glycosides are natural compounds used for the treatment of cardiovascular disorders. Although originally prescribed for cardiovascular diseases, more recently, they have been rediscovered for their potential use in the treatment of cancer. Proscillaridin A (PSD-A), a cardiac glycoside component of Urginea maritima, has been reported to exhibit anticancer activity. However, the cellular targets and anticancer mechanism of PSD-A in various cancers including lung cancer remain largely unexplored. In the present study, we found that PSD-A inhibits growth and induces apoptosis in A549 lung adenocarcinoma cells. The anticancer activity of PSD-A was found to be associated with the activation of JNK, induction of ER stress, mitochondrial dysfunction, and inhibition of STAT3 activation. PSD-A induces oxidative stress as evidenced from ROS generation, GSH depletion, and decreased activity of TrxR1. PSD-A-mediated ER stress was verified by increased phosphorylation of eIF2α and expression of its downstream effector proteins ATF4, CHOP, and caspases-4. PSD-A triggered apoptosis by inducing JNK (1/2) activation, increasing bax/bcl-2 ratio, dissipating mitochondrial membrane potential, and inducing cleavage of caspases and PARP. Further study revealed that PSD-A inhibits both constitutive and inducible STAT3 activations and decreases STAT3 DNA-binding activity. Moreover, PSD-A-mediated inhibition of STAT3 activation was found to be associated with increased SHP-1 expression, decreased phosphorylation of Src, and binding of PSD-A with STAT3 SH2 domain. Finally, STAT3 knockdown by shRNA inhibited growth and enhanced apoptotic efficacy of PSD-A. Taken together, the data suggest that PSD-A could be developed into a potential therapeutic agent against lung adenocarcinoma.

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Section: Discussionmentioning

confidence: 99%

Proscillaridin A Promotes Oxidative Stress and ER Stress, Inhibits STAT3 Activation, and Induces Apoptosis in A549 Lung Adenocarcinoma Cells

Maryam

Mehmood

Yan

et al. 2018

Oxidative Medicine and Cellular Longevity

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show abstract

“…Rhein reportedly decreases ATP production, reduces the mitochondrial transmembrane potential, up-regulates the release of cytochrome c (Cyto c), and activates caspase-3 to induce apoptosis in Hep-G2 cells; moreover, the mitochondrial permeability transition was found to play a critical role in the rhein-induced cell death of these cells [ 41 ]. A recent investigation showed that rhein-induced apoptosis is caspase-dependent and involves ER-stress associated pathways and increased intracellular calcium levels in HL-7702 cells [ 42 ]. The same study also found that rhein could induce apoptosis in HL-7702 cells through oxidative stress-involved mitochondria-mediated apoptotic processes.…”

Section: Discussionmentioning

confidence: 99%

Rhein Induces Oxidative Stress and Apoptosis in Mouse Blastocysts and Has Immunotoxic Effects during Embryonic Development

Huang

Chan

2017

IJMS

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Rhein, a glucoside chemical compound found in a traditional Chinese medicine derived from the roots of rhubarb, induces cell apoptosis and is considered to have high potential as an antitumor drug. Several previous studies showed that rhein can inhibit cell proliferation and trigger mitochondria-related or endoplasmic reticulum (ER) stress-dependent apoptotic processes. However, the side effects of rhein on pre- and post-implantation embryonic development remain unclear. Here, we show that rhein has cytotoxic effects on blastocyst-stage mouse embryos and induces oxidative stress and immunotoxicity in mouse fetuses. Blastocysts incubated with 5–20 μM rhein showed significant cell apoptosis, as well as decreases in their inner cell mass cell numbers and total cell numbers. An in vitro development assay showed that rhein affected the developmental potentials of both pre- and post-implantation embryos. Incubation of blastocysts with 5–20 μM rhein was associated with increased resorption of post-implantation embryos and decreased fetal weight in an embryo transfer assay. Importantly, in an in vivo model, intravenous injection of dams with rhein (1, 3, and 5 mg/kg body weight/day) for four days resulted in apoptosis of blastocyst-stage embryos, early embryonic developmental injury, and decreased fetal weight. Intravenous injection of dams with 5 mg/kg body weight/day rhein significantly increased the total reactive oxygen species (ROS) content of fetuses and the transcription levels of antioxidant proteins in fetal livers. Additional work showed that rhein induced apoptosis through ROS generation, and that prevention of apoptotic processes effectively rescued the rhein-induced injury effects on embryonic development. Finally, the transcription levels of the innate-immunity related genes, CXCL1, IL-1 β and IL-8, were down-regulated in the fetuses of dams that received intravenous injections of rhein. These results collectively show that rhein has the potential to induce embryonic cytotoxicity and induce oxidative stress and immunotoxicity during the development of mouse embryos.

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“…This may be due to the low cytotoxicity selectivity of rhubarb at high doses. Studies have shown that the monomer components of rhubarb had significant cytotoxicity to human normal liver LO2 cells, HL-7702 cells [73] and human renal tubular epithelial HK-2 cells [74,75] in a dose-and time-dependent manner. Therefore, more attention should be paid to developing targeted agents from rhubarb to reduce the distribution of drugs in noncancerous tissues.…”

Section: Antitumor Activitymentioning

confidence: 99%

What we already know about rhubarb: a comprehensive review

et al. 2020

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Rhubarb (also named Rhei or Dahuang), one of the most ancient and important herbs in traditional Chinese medicine (TCM), belongs to the Rheum L. genus from the Polygonaceae family, and its application can be traced back to 270 BC in "Shen Nong Ben Cao Jing". Rhubarb has long been used as an antibacterial, anti-inflammatory, anti-fibrotic and anticancer medicine in China. However, for a variety of reasons, such as origin, variety and processing methods, there are differences in the effective components of rhubarb, which eventually lead to decreased quality and poor efficacy. Additionally, although some papers have reviewed the relationship between the active ingredients of rhubarb and pharmacologic actions, most studies have concentrated on one or several aspects, although there has been great progress in rhubarb research in recent years. Therefore, this review aims to summarize recent studies on the geographic distribution, taxonomic identification, pharmacology, clinical applications and safety issues related to rhubarb and provide insights into the further development and application of rhubarb in the future.

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Rhein triggers apoptosis via induction of endoplasmic reticulum stress, caspase-4 and intracellular calcium in primary human hepatic HL-7702 cells

Cited by 21 publications

References 29 publications

Proscillaridin A Promotes Oxidative Stress and ER Stress, Inhibits STAT3 Activation, and Induces Apoptosis in A549 Lung Adenocarcinoma Cells

Proscillaridin A Promotes Oxidative Stress and ER Stress, Inhibits STAT3 Activation, and Induces Apoptosis in A549 Lung Adenocarcinoma Cells

Rhein Induces Oxidative Stress and Apoptosis in Mouse Blastocysts and Has Immunotoxic Effects during Embryonic Development

What we already know about rhubarb: a comprehensive review

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