Isoalantolactone, a sesquiterpene lactone, induces apoptosis in SGC-7901 cells via mitochondrial and phosphatidylinositol 3-kinase/Akt signaling pathways

Rasul, Azhar; Khan, Muhammad Tanveer; B, Yu; Ali, Muhammad; Yang, Bo; Yang, Hong; Ma, Tonghui

doi:10.1007/s12272-013-0217-0

Cited by 48 publications

(36 citation statements)

References 39 publications

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“…In the present study, SGC7901 cells were treated with doxorubicin, and the rate of apoptosis increased when P-REX2a was knocked down. Bcl-2 and Bax are anti-apoptotic and pro-apoptotic effectors, respectively, and are important regulators in the PI3K/Akt signaling pathway (25). The expression of Bcl-2 was decreased and the expression of Bax was increased in cells transfected with P-REX2a-siRNA compared with the negative control.…”

Section: Discussionmentioning

confidence: 99%

Interference of P-REX2a may inhibit proliferation and reverse the resistance of SGC7901 cells to doxorubicin

Zhou

et al. 2017

Oncol Lett

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Abstract. Drug resistance inhibits the efficacy of doxorubicin in gastric cancer. Phosphatidylinositol 3,4,5-trisphosphate RAC exchanger 2a (P-REX2a) activates the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) signaling pathway by binding to and inactivating phosphatase and tensin homolog (PTEN), which functions as a tumor promoter in a number of types of cancer. However, there is no research concerning the association between P-REX2a expression and drug resistance in gastric cancer. In the present study, the expression of P-REX2a in clinical gastric cancer tissues was detected, and the mechanism of doxorubicin resistance in the gastric cancer cell line SGC7901 was investigated. Using reverse transcription-quantitative polymerase chain reaction and western blotting, it was demonstrated that the mRNA and protein expression of P-REX2a was increased in gastric cancer tissues. MTT assays were also used to determine proliferation, and proliferation was revealed to be reduced following transfection of P-REX2a small interfering (si)RNA. When the cells were treated with 0.3 µM doxorubicin for 24 h, the rate of apoptosis in the siRNA-transfected groups significantly increased and no marked changes in of PTEN and Akt expression were observed. By contrast, the activity of PTEN increased, and the expression of p-Akt (S473) decreased in the P-REX2a siRNA-transfected group compared with the control. The detection of PTEN enzymatic activity in the present study was based on phosphatidylinositol-3,4,5-trisphosphate. Therefore, it was concluded that P-REX2a may participate in the generation of resistance to doxorubicin in gastric cancer, and this may be associated with the upregulation of the PI3K/Akt signaling pathway via inactivation of PTEN.

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Section: Discussionmentioning

confidence: 99%

Interference of P-REX2a may inhibit proliferation and reverse the resistance of SGC7901 cells to doxorubicin

Zhou

et al. 2017

Oncol Lett

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“…Isoalantolactone has been reported to induce cell death in several human cancer cell lines, such as PANC-1 cells (6), human prostate cancer cells (8), and human gastric adenocarcinoma SGC-7901 cells (9) via cell cycle arrest and induction of apoptosis. In line with previous reports, we found that isoalantolactone arrested the cell cycle at the S and mainly the G2/M phase in U2OS cells.…”

Section: Discussionmentioning

confidence: 99%

“…A previous study by Khan et al showed that isoalantolactone did not exert any acute or chronic cytotoxicity in mouse liver and kidney (6). Although there are a few reports on the anticancer activities of isoalantolactone (6)(7)(8)(9)(10), there is no report available on the anti-osteosarcoma effect of isoalantolactone.…”

Section: Introductionmentioning

confidence: 99%

Isoalantolactone inhibits constitutive NF-κB activation and induces reactive oxygen species-mediated apoptosis in osteosarcoma U2OS cells through mitochondrial dysfunction

Khan

Rasul

et al. 2014

Oncology Reports

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Abstract.Human osteosarcoma is an aggressive tumor which frequently resists chemotherapy; therefore, the search for new agents for its treatment is of great importance. Isoalantolactone, isolated from Inula spp., has been reported to inhibit the growth of several types of cancer cells. However, no prior research has been conducted to demonstrate the antiproliferative potential of isoalantolactone on osteosarcoma. The present study is the first to investigate the effects of isoalantolactone on cell viability in human osteosarcoma U2OS, MG-63 and Saos-2 cells, and its mechanism of action in U2OS cells. Our results demonstrated that isoalantolactone triggered S and mainly G2/M cell cycle phase arrest, accompanied by the downregulation of the expression of cyclin B1 at the protein and mRNA levels. Moreover, isoalantolactone induced apoptosis that was associated with reactive oxygen species (ROS) generation and the dissipation of mitochondrial membrane potential (MMP). Furthermore, our results indicated that this compound upregulated DR5, FADD and cleaved caspase-8, increased the interation between DR5 and FADD, and inhibited the expression of nuclear NF-κBp65. We also found that isoalantolactone-induced apoptosis was associated with the downregulation of Bcl-2 and upregulation of Bax, which finally led to the activation of caspase-3 and its downstream substrate, PARP, in osteosarcoma U2OS cells. Isoalantolactone-induced apoptosis was markedly abrogated when the cells were pretreated with N-acetylcysteine (NAC), a specific ROS inhibitor, suggesting that the apoptosis-inducing effect of isoalantolactone in osteosarcoma cells was mediated by reactive oxygen species. Taken together, our data demonstrated that isoalantolactone induces ROS-dependent apoptosis in U2OS cells via a novel mechanism involving inhibition of NF-κBp65 and provide the rationale for further in vivo and preclinical investigation of isoalantolactone against osteosarcoma.

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“…Isoalantolactone inhibits phosphorylation of PI3K/Akt on SGC-7901 cells (98), and alantolactone seems to induce detoxifying enzymes via activation of the PI3K and JNK signaling pathways (89). In cervical carcinoma HeLa cell line, oridonin may suppress constitutively activated targets of phosphatidylinositol 3-kinase (Akt, FOXO, and GSK3; ref.…”

Section: Growth Factors and Their Receptors Family Pathwaymentioning

confidence: 99%

Targeting Apoptosis Pathways in Cancer and Perspectives with Natural Compounds from Mother Nature

Millimouno

Dong

Liu

et al. 2014

Cancer Prevention Research

236

168

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Although the incidences are increasing day after day, scientists and researchers taken individually or by research group are trying to fight against cancer by several ways and also by different approaches and techniques. Sesquiterpenes, flavonoids, alkaloids, diterpenoids, and polyphenolic represent a large and diverse group of naturally occurring compounds found in a variety of fruits, vegetables, and medicinal plants with various anticancer properties. In this review, our aim is to give our perspective on the current status of the natural compounds belonging to these groups and discuss their natural sources, their anticancer activity, their molecular targets, and their mechanism of actions with specific emphasis on apoptosis pathways, which may help the further design and conduct of preclinical and clinical trials. Unlike pharmaceutical drugs, the selected natural compounds induce apoptosis by targeting multiple cellular signaling pathways including transcription factors, growth factors, tumor cell survival factors, inflammatory cytokines, protein kinases, and angiogenesis that are frequently deregulated in cancers and suggest that their simultaneous targeting by these compounds could result in efficacious and selective killing of cancer cells. This review suggests that they provide a novel opportunity for treatment of cancer, but clinical trials are still required to further validate them in cancer chemotherapy. Cancer Prev Res; 7(11);

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Isoalantolactone, a sesquiterpene lactone, induces apoptosis in SGC-7901 cells via mitochondrial and phosphatidylinositol 3-kinase/Akt signaling pathways

Cited by 48 publications

References 39 publications

Interference of P-REX2a may inhibit proliferation and reverse the resistance of SGC7901 cells to doxorubicin

Interference of P-REX2a may inhibit proliferation and reverse the resistance of SGC7901 cells to doxorubicin

Isoalantolactone inhibits constitutive NF-κB activation and induces reactive oxygen species-mediated apoptosis in osteosarcoma U2OS cells through mitochondrial dysfunction

Targeting Apoptosis Pathways in Cancer and Perspectives with Natural Compounds from Mother Nature

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