Xanthatin Induces G2/M Cell Cycle Arrest and Apoptosis in Human Gastric Carcinoma MKN-45 Cells

Zhang, Lei; Li, Tao; Ruan, Junshan; Li, Weidong; Wu, Yu; Yan, Linggeng; Zhang, Feng; Fan, Fangtian; Zheng, Shizhong; Wang, Aiyun; Lu, Yin

doi:10.1055/s-0031-1298481

Cited by 26 publications

(16 citation statements)

References 22 publications

(27 reference statements)

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“…These findings provide support for the consideration of (−)-xanthatin as an intriguing chemical entity for inclusion with the other sesquiterpene lactones in future cancer clinical trials (Zhang et al, 2005; Ghantous et al, 2010). In support of this, several possibilities of (−)-xanthatin’s potential for cancer prevention and therapy are being reported (Nibret et al, 2011; Zhang et al, 2012a,b). …”

Section: Discussionmentioning

confidence: 82%

(−)-Xanthatin up-regulation of the GADD45γ tumor suppressor gene in MDA-MB-231 breast cancer cells: Role of topoisomerase IIα inhibition and reactive oxygen species

et al. 2013

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Previously, we reported that (−)-xanthatin, a naturally occurring xanthanolide present in the Cocklebur plant, exhibits potent anti-proliferative effects on human breast cancer cells, accompanied by an induction of the growth arrest and DNA damage-inducible gene 45γ (GADD45γ), recognized recently as a novel tumor suppressor gene. However, the mechanisms mediating this activation were unknown. Topoisomerase IIα (Topo IIα) inhibition has been reported to produce a cell death response accompanied by an atypical DNA laddering fragmentation profile, similar to that noted previously for (–)-xanthatin. Therefore we hypothesized that (−)-xanthatin’s GADD45γ activation was mediated through the Topo IIα pathway. Here, we identify that (−)-xanthatin does function as a catalytic inhibitor of Topo IIα, promoting DNA damage. In addition, reactive oxygen species (ROS) were elevated in cells treated with this agent. Mechanistically, it was determined that the induced levels of GADD45γ mRNA resulting from (−)-xanthatin exposures were stabilized by coordinately produced ROS, and that the consequent induction of GADD45γ mRNA, GADD45γ protein and ROS generation were abrogated by co-treatment with N-acetyl-l-cysteine. Taken together, the data support the concept that Topo IIα inhibition by (−)-xanthatin is a trigger that stimulates expression of DNA damage-inducible GADD45γ mRNA and that concomitantly produced ROS act downstream to further enhance the GADD45γ mRNA/GADD45γ protein induction process, resulting in breast cancer cell death.

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Section: Discussionmentioning

confidence: 82%

(−)-Xanthatin up-regulation of the GADD45γ tumor suppressor gene in MDA-MB-231 breast cancer cells: Role of topoisomerase IIα inhibition and reactive oxygen species

et al. 2013

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“…This is of considerable interest as we had previously shown that consumption of n-3 decreased the activity of nuclear factor kappa B (NFκB) in isolated lymphocytes of patients with early stage CLL and would be expected to slow the progression of the disease [12]. Studies have shown that inhibition of NFκB activation leads to cell cycle arrest at the G2/M phase aiding to both growth-inhibition and cell death [23,24]. Future studies will be aimed in determining if n-3 can slow the progression and growth of CLL and whether growth-inhibition is mediated through suppression of NFκB activation and G2/M arrest.…”

Section: Discussionmentioning

confidence: 99%

Omega 3 fatty acids increase the chemo-sensitivity of B-CLL-derived cell lines EHEB and MEC-2 and of B-PLL-derived cell line JVM-2 to anti-cancer drugs doxorubicin, vincristine and fludarabine

Fahrmann

Hardman

2013

Lipids Health Dis

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BackgroundB-Cell chronic lymphocytic leukemia (CLL) is the most common form of leukemia in the United States. Clinical treatment of CLL is often limited due to drug resistance and severe therapy-induced toxicities. We hypothesized that the omega 3 (n-3) fatty acids, eicosapentaenoic acid (EPA) and/or docosahexaenoic acid (DHA), would increase the sensitivity of malignant B-lymphocytes to anti-cancer drugs doxorubicin, vincristine and/or fludarabine in vitro and that increased sensitivity is achieved by alterations in cell-cycle progression leading to growth inhibition and/or enhanced cell death. We further postulate that enhanced sensitivity is dependent on the formation of lipid peroxides and to the generation of reactive oxygen species (ROS).MethodsIn the present study, B-CLL-derived leukemic cell lines EHEB and MEC-2 and the B-Prolymphocytic leukemic-derived (PLL) cell line JVM-2 were tested for in vitro sensitivity against doxorubicin, vincristine or fludarabine in the presence or absence of vehicle, arachidonic acid (omega 6), EPA or DHA. Cell cycle analysis and Annexin-V assays were performed to determine cell cycle progression and % apoptotic cells, respectively. Assays for malondialdehyde, a measure of lipid peroxidation, and DCF fluorescence assays, a measure of intracellular ROS, were performed to determine if enhanced sensitivity of cells to the drugs by n-3 was dependent on the formation of ROS.ResultsOur results indicated that: 1) EPA and DHA differentially sensitized B-leukemic cell lines EHEB, JVM-2 and MEC-2 to doxorubicin, vincristine and fludarabine in vitro; 2) n-3 alone and with drug treatment increased cell death and induced G2/M arrest in a cell-type specific manner; 3) lipid peroxidation increased in the presence of n-3; 4) there was higher lipid peroxidation in MEC-2 cells in presence of DHA and doxorubicin than with either alone; 5) n-3 increased generation of ROS in MEC-2, and 6) the addition of vitamin-E abrogated the increase in ROS generation and chemo-sensitivity of MEC-2 to doxorubicin by DHA.ConclusionN-3’s are promising chemo-sensitizing agents for the treatment of CLL. Selective enhancement of chemo-sensitivity of EHEB, JVM-2 and MEC-2 to drugs by n-3 that is not dependent on increased lipid peroxidation and ROS generation indicates alternative mechanisms by which n-3 enhances chemo-sensitivity.

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“…Previously, we demonstrated that xanthatin significantly induced cell cycle arrest and caspase-dependent apoptosis in human lung and gastric cancer, as well as murine melanoma [9,11,12]. However, it remains largely unclear whether inhibition of GSK3β is essential for the anticancer effect of xanthatin.…”

Section: Introductionmentioning

confidence: 99%

Concerted Suppression of STAT3 and GSK3β Is Involved in Growth Inhibition of Non-Small Cell Lung Cancer by Xanthatin

Fan

Liu

et al. 2013

PLoS ONE

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Xanthatin, a sesquiterpene lactone purified from Xanthium strumarium L., possesses prominent anticancer activity. We found that disruption of GSK3β activity was essential for xanthatin to exert its anticancer properties in non-small cell lung cancer (NSCLC), concurrent with preferable suppression of constitutive activation of STAT3. Interestingly, inactivation of the two signals are two mutually exclusive events in xanthatin-induced cell death. Moreover, we surprisingly found that exposure of xanthatin failed to trigger the presumable side effect of canonical Wnt/β-Catenin followed by GSK3β inactivation. We further observed that the downregulation of STAT3 was required for xanthatin to fine-tune the risk. Thus, the discovery of xanthatin, which has ability to simultaneously orchestrate two independent signaling cascades, may have important implications for screening promising drugs in cancer therapies.

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Xanthatin Induces G2/M Cell Cycle Arrest and Apoptosis in Human Gastric Carcinoma MKN-45 Cells

Cited by 26 publications

References 22 publications

(−)-Xanthatin up-regulation of the GADD45γ tumor suppressor gene in MDA-MB-231 breast cancer cells: Role of topoisomerase IIα inhibition and reactive oxygen species

(−)-Xanthatin up-regulation of the GADD45γ tumor suppressor gene in MDA-MB-231 breast cancer cells: Role of topoisomerase IIα inhibition and reactive oxygen species

Omega 3 fatty acids increase the chemo-sensitivity of B-CLL-derived cell lines EHEB and MEC-2 and of B-PLL-derived cell line JVM-2 to anti-cancer drugs doxorubicin, vincristine and fludarabine

Concerted Suppression of STAT3 and GSK3β Is Involved in Growth Inhibition of Non-Small Cell Lung Cancer by Xanthatin

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