Timosaponin AIII mediates caspase activation and induces apoptosis through JNK1/2 pathway in human promyelocytic leukemia cells

Flavokawain B (FKB), a natural kava chalcone, shows potent antitumor activity in various types of cancer, although the mechanism of action remains unclear. In this study, we report that FKB has profound effects on the metabolic state of human thyroid cancer (TCa) cells, leading to high autophagy flux through upregulation of AMP‐activated protein kinase, which in turn inhibits mTOR and activates Beclin‐1 in TCa cells. We further report that the autophagy induced by FKB plays a prosurvival role in TCa cells both in vitro and in vivo. In conclusion, our findings provide evidence that combination treatment with FKB and pharmacological autophagy inhibitors will be a potential therapeutic strategy for the treatment of TCa.

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“…Flavokawain B induces apoptosis in a variety of cancer cells . We therefore determined whether FKB also induces apoptosis of TCa cells.…”

Section: Resultsmentioning

confidence: 99%

“…Flavokawain B induces apoptosis in a variety of cancer cells. [19][20][21] We therefore determined whether FKB also induces apoptosis of TCa cells. Increases in apoptosis were observed in three cell lines in early (annexin V+/propidium iodide [PI]−) and late (annexin V+/PI+) stages with FKB at 24 h ( Fig.…”

Section: Flavokawain B Inhibits Growth Of Tca Cellsmentioning

confidence: 99%

Adenosine 5'‐monophosphate‐activated protein kinase‐dependent mTOR pathway is involved in flavokawain B‐induced autophagy in thyroid cancer cells

Liu

Sha

et al. 2018

Cancer Science

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“…Cantharidin and CA are the selective inhibitors of serine/threonine phosphatase 1 and 2A, and represent an important aspect of cell apoptosis . Apoptosis is a procedure of programmed cell death involving caspases occurring in cells as inactive proenzymes . Previous studies have shown that cantharidin induced apoptosis through blocks the cell cycle, and this effect is mediated by cell cycle arrest at the G2/M phase .…”

Section: Discussionmentioning

confidence: 99%

“…32 Thus, SK-Hep-1 cells are very critical cell lines applied in investigation, and the involving caspases occurring in cells as inactive proenzymes. 35,36 Previous studies have shown that cantharidin induced apoptosis through blocks the cell cycle, and this effect is mediated by cell cycle arrest at the G2/M phase. 17,37 CA is a phosphatase inhibitor and thus induces cytochrome c release and elevated activation of caspase-3 in the pancreatic beta cell line HIT.…”

Section: Discussionmentioning

confidence: 99%

Cantharidic acid induces apoptosis through the p38 MAPK signaling pathway in human hepatocellular carcinoma

Feng

Hsieh

Chen

et al. 2017

Environmental Toxicology

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Cantharidin analogs exhibit anticancer activities, including apoptosis. However, the molecular mechanisms underlying the effects of cantharidic acid (CA), a cantharidin analog, on apoptosis in hepatocellular carcinoma (HCC) cells are unclear. Thus, in this study, we evaluated the anticancer activities of CA by investigating its ability to trigger apoptosis in SK-Hep-1 cells. Our data demonstrated that CA effectively inhibited the proliferation of SK-Hep-1 cells in a dose-dependent manner. Furthermore, CA effectively triggered cell cycle arrest and induced apoptosis, as determined by flow cytometric analysis. Western blotting revealed that CA significantly activated proapoptotic signaling including caspase-3, -8, and -9 in SK-Hep-1 cells. Moreover, treatment of SK-Hep-1 cells with CA induced the activation of ERK, p38, and c-Jun N-terminal kinase. Moreover, the inhibition of p38 by specific inhibitors abolished CA-induced cell apoptosis. In conclusion, our results indicated that CA induces apoptosis in SK-Hep-1 cells through a p38-mediated apoptotic pathway and could be a new HCC therapeutic agent.

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“…Rhizoma Anemarrhenae (Zhimu in Chinese), a wellknown traditional Chinese medicinal herb, which is officially listed in the Chinese Pharmacopoeia, has been effectively used for febrile diseases in oriental clinical practices. Timosaponin A-III (TAIII), a steroidal saponin isolated from the rhizomes of Anemarrhena asphodeloides (AA), has been credited with a wide spectrum of bioactivities, including improving learning and memory (16), inhibiting inflammation (17), suppressing allergic reaction (18), controlling hyperglycemic (19,20), activating autophagy (21) and inducing cancer cells apoptosis (22)(23)(24). However, the ability of TAIII to reverse MDR has not been reported.…”

Section: Introductionmentioning

confidence: 99%

Timosaponin A-III reverses multi-drug resistance in human chronic myelogenous leukemia K562/ADM cells via downregulation of MDR1 and MRP1 expression by inhibiting PI3K/Akt signaling pathway

Chen

Xing

Wang

et al. 2016

International Journal of Oncology

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One of the major causes of failure in chemotherapy for patients with human chronic myelogenous leukemia (CML) is the acquisition of multidrug resistance (MDR). MDR is often associated with the overexpression of drug efflux transporters of the ATP-binding cassette (ABC) protein family. Timosaponin A-III (TAIII), a saponin isolated from the rhizome of Anemarrhena asphodeloides, has previously demonstrated the ability to suppress certain human tumor processes and the potential to be developed as an anticancer agent. Nevertheless, the ability of TAIII to reverse MDR has not yet been explored. In this study, the adriamycin (ADM) resistance reversal effect of TAIII in human CML K562/ADM cells and the underlying mechanism was investigated. The Cell Counting Kit-8 (CCK-8) assay showed that TAIII had a reversal effect on the drug resistance of K562/ADM cells. Flow cytometry assay showed increased intracellular accumulation of ADM after cells were pretreated with TAIII, and the changes in the accumulation of rhodamine-123 (Rho-123) and 5(6)-carboxyfluorescein diacetate (CFDA) dye in K562/ADM cells were determined to be similar to the changes of intracellular accumulation of ADM. After pretreatment of cells with TAIII, the decreasing expression of P-gp and MRP1 mRNA was examined by reverse transcription polymerase chain reaction (RT-PCR). Western blotting showed TAIII inhibiting P-gp and MRP1 expression depended on the PI3K/Akt signaling pathway by decreasing the activity of p-Akt. Moreover, wortmannin an inhibitor of PI3K/Akt signaling pathway has a strong inhibitory effect on the expression of p-Akt, P-gp and MRP1. Besides, the combined treatment with TAIII did not have an affect on wortmannin downregulation of p-Akt, P-gp and MRP1. Taken together, our findings demonstrate, for the first time, that TAIII induced MDR reversal through inhibition of P-gp and MRP1 expression and function with regained adriamycin sensitivity which might mainly correlate to the regulation of PI3K/Akt signaling pathway.

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Timosaponin AIII mediates caspase activation and induces apoptosis through JNK1/2 pathway in human promyelocytic leukemia cells

Cited by 26 publications

References 38 publications

Adenosine 5'‐monophosphate‐activated protein kinase‐dependent mTOR pathway is involved in flavokawain B‐induced autophagy in thyroid cancer cells

Adenosine 5'‐monophosphate‐activated protein kinase‐dependent mTOR pathway is involved in flavokawain B‐induced autophagy in thyroid cancer cells

Cantharidic acid induces apoptosis through the p38 MAPK signaling pathway in human hepatocellular carcinoma

Timosaponin A-III reverses multi-drug resistance in human chronic myelogenous leukemia K562/ADM cells via downregulation of MDR1 and MRP1 expression by inhibiting PI3K/Akt signaling pathway

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