Polyphyllin D is a potent apoptosis inducer in drug-resistant HepG2 cells

Cheung, Jenny Y.N.; Ong, Rose; Suen, Y. K.; Ooi, Vincent E.C.; Wong, H. N. C.; Mak, Thomas C. W.; Fung, Kwok‐Pui; Yu, Biao; Kong, Siu‐Kai

doi:10.1016/j.canlet.2004.06.042

Cited by 132 publications

(25 citation statements)

References 18 publications

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“…In order to further confirm that the cell death induced by DHA + DOX was apoptosis, Annexin V/PI double staining was used to detect the extroversion of phosphatidyl serine on the cell membrane and the PI-specific stained cell nuclei after rupture of the membrane, indicating apoptosis (11,12). As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

In vitro and in vivo inhibition of tumor cell viability by combined dihydroartemisinin and doxorubicin treatment, and the underlying mechanism

et al. 2016

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The natural extract artemisinin and its derivatives have good anticancer activity. The present study aimed to investigate the in vitro inhibitory effects of combined dihydroartemisinin (DHA) and doxorubicin (DOX) treatment on a variety of tumor cell lines (HeLa, OVCAR-3, MCF-7, PC-3 and A549), as well as the underlying mechanisms. In addition, the in vivo effects of DHA and DOX were evaluated using a mouse HeLa tumor model. The HeLa, OVCAR-3, MCF-7, PC-3 and A549 cells were treated with a combination of DHA and DOX, and the effect on cell viability was detected by Cell Counting kit-8. The cells were observed under a fluorescence microscope after staining with Hoechst 33258 dye to observe morphological changes in the nuclei in order to determine whether the cells in the treatment group exhibited apoptosis. Apoptosis of the cells was further detected by flow cytometry, and statistical analysis was performed. The specific inhibitors of caspase-3, −8 and −9 were used to determine the intrinsic and extrinsic pathways of cell apoptosis. The cervical cancer HeLa cells treated with the combination of DHA and DOX showed up to a 91.5% decrease in viability, which was higher than that of the same cells treated with DHA or DOX alone at the same concentration, respectively (P<0.01). The optimal concentrations of the drugs used in combination were DHA at 10 µg/ml and DOX at 10 µg/ml. DHA + DOX also had a significant inhibitory effect on the ovarian cancer (OVCAR-3), breast cancer (MCF-7), lung cancer (A549) and prostate cancer (PC-3) cells. The images observed under fluorescence microscope after Hoechst 33258 staining showed marked pyknosis in the cells treated with DHA + DOX, similar to that when treated with DHA or DOX alone, which is typical in apoptosis. As determined by flow cytometry, the apoptotic rate of the cells treated with DHA + DOX at optimal concentrations was up to 90%, which was significantly higher than that of the cells treated with DHA or DOX alone at the same concentration. Caspase-9 and −3 inhibitors significantly increased the viability of the cells treated with DHA + DOX. At 6 days post-intratumoral injection of DHA + DOX, the tumor volume was markedly reduced. In vivo toxicity results revealed that the combination of the drugs had basically no effect on the body weight of the mice and had no significant toxicity on the liver, spleen, kidneys and heart of the animals. Overall, the combination of DHA and DOX markedly inhibited the viability of the HeLa, OVCAR-3, MCF-7, PC-3 and A549 cells, and acted on the HeLa cells through the intrinsic apoptotic pathway mediated by caspase-9 and caspase-3. DHA + DOX also had a significant treatment effect in vivo. This study provides a novel idea for the development of a clinical medication against several types of cancer.

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Section: Resultsmentioning

confidence: 99%

In vitro and in vivo inhibition of tumor cell viability by combined dihydroartemisinin and doxorubicin treatment, and the underlying mechanism

et al. 2016

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“…Some phytochemicals, such as PEITC, ganoderic acid T, and polyphyllin D, induce apoptosis via caspases, mitochondrial dysfunction and/or activation of the tumor suppressor gene p53 (Yu et al, 1998; Cheung et al, 2005; Lee et al, 2005; Tang et al, 2006; Ma et al, 2009). PEITC and other structurally related isothiocyanates, except phenyl isothiocyanate (PITC), are capable of inducing apoptosis and Poly (ADP-ribose) polymerase (PARP) cleavage in a dose-dependent manner in HeLa cells through a caspase-3-dependent mechanism (Yu et al, 1998).…”

Section: Dietary Phytochemicals Activate Signaling Pathways To Supmentioning

confidence: 99%

Dietary phytochemicals and cancer prevention: Nrf2 signaling, epigenetics, and cell death mechanisms in blocking cancer initiation and progression

Lee

Khor

Shu

et al. 2013

Pharmacology & Therapeutics

225

166

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Reactive metabolites from carcinogens and oxidative stress can drive genetic mutations, genomic instability, neoplastic transformation, and ultimately carcinogenesis. Numerous dietary phytochemicals in vegetables/fruits have been shown to possess cancer chemopreventive effects in both preclinical animal models and human epidemiological studies. These phytochemicals could prevent the initiation of carcinogenesis via either direct scavenging of reactive oxygen species/reactive nitrogen species (ROS/RNS) or, more importantly, the induction of cellular defense detoxifying/antioxidant enzymes. These defense enzymes mediated by Nrf2-antioxidative stress and anti-inflammatory signaling pathways can contribute to cellular protection against ROS/RNS and reactive metabolites of carcinogens. In addition, these compounds would kill initiated/transformed cancer cells in vitro and in in vivo xenografts via diverse anti-cancer mechanisms. These mechanisms include the activation of signaling kinases (e.g., JNK), caspases and the mitochondria damage/cytochrome c pathways. Phytochemicals may also have anti-cancer effects by inhibiting the IKK/NF-κB pathway, inhibiting STAT3, and causing cell cycle arrest. In addition, other mechanisms may include epigenetic alterations (e.g., inhibition of HDACs, miRNAs, and the modification of the CpG methylation of cancer-related genes). In this review, we will discuss: the current advances in the study of Nrf2 signaling; Nrf2-deficient tumor mouse models; the epigenetic control of Nrf2 in tumorigenesis and chemoprevention; Nrf2-mediated cancer chemoprevention by naturally occurring dietary phytochemicals; and the mutation or hyper-expression of the Nrf2–Keap1 signaling pathway in advanced tumor cells. The future development of dietary phytochemicals for chemoprevention must integrate in vitro signaling mechanisms, relevant biomarkers of human diseases, and combinations of different phytochemicals and/or non-toxic therapeutic drugs, including NSAIDs.

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“…1a) was the active ingredient isolated from the rhizome of Paris polyphylla. PD exhibits anticancer activities in different cancer cell lines (Cheung et al 2005;Lee et al 2005;Siu et al 2008). In the past few years, PD has acquired a lot of attention because it directly triggers mitochondrial membrane permeabilization for the induction of apoptosis (Ong et al 2008).…”

Section: Introductionmentioning

confidence: 98%

Polyphyllin D induces apoptosis in human erythrocytes through Ca2+ rise and membrane permeabilization

et al. 2012

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Polyphyllin D (PD) is a potent anticancer agent isolated from a traditional medicinal herb Paris polyphylla that has been used in China for many years to treat cancer. PD is not a substrate of p-glycoprotein, and it can bypass the multi-drug resistance in cancer cell line R-HepG2. However, the effect of PD on the induction of cell death in human erythrocytes remains unknown. Given that PD is a small molecule that can depolarize the mitochondrial membrane potential and release apoptosis-inducing factor (AIF) in isolated mitochondria, we hypothesized that the apoptogenic effect of PD in human erythrocytes devoid of mitochondria would be minimal. This study therefore tried to evaluate the in vitro effect of PD on hemolysis and apoptosis in human erythrocytes. Apoptosis in human red blood cells (RBCs), also known as eryptosis or erythroptosis, after PD treatment was determined by flow cytometry and confocal microscopy for the phosphatidyl-serine externalization and other apoptosis feature events. False to our prediction, PD caused hemolysis and eryptosis/erythroptosis in human RBCs. Mechanistically, elevation in the cytosolic Ca²⁺ ion level seems to be a key but not the only mediator in the PD-mediated eryptosis/erythroptosis because depletion of the external Ca²⁺ could not eliminate the PD effect. Also, PD was able to permeabilize the membrane of RBC ghosts in a way similar to digitonin. Taken together, we report here for the first time the toxicity of PD in human RBCs as well as its underlying mechanism for the hemolysis and eryptosis/erythroptosis.

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Polyphyllin D is a potent apoptosis inducer in drug-resistant HepG2 cells

Cited by 132 publications

References 18 publications

In vitro and in vivo inhibition of tumor cell viability by combined dihydroartemisinin and doxorubicin treatment, and the underlying mechanism

In vitro and in vivo inhibition of tumor cell viability by combined dihydroartemisinin and doxorubicin treatment, and the underlying mechanism

Dietary phytochemicals and cancer prevention: Nrf2 signaling, epigenetics, and cell death mechanisms in blocking cancer initiation and progression

Polyphyllin D induces apoptosis in human erythrocytes through Ca2+ rise and membrane permeabilization

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