Alantolactone Induces Apoptosis and Cell Cycle Arrest on Lung Squamous Cancer SK‐MES‐1 Cells

Zhao, Peng; Pan, Zhenxiang; Luo, Yungang; Zhang, Leilei; Li, Xin; Zhang, Guangxin; Zhang, Yifan; Cui, Ranji; Sun, Mei; Zhang, Xingyi

doi:10.1002/jbt.21685

Cited by 35 publications

(22 citation statements)

References 28 publications

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“…Tumor cell toxicity is a well-known property of ATL, but the effective concentrations reported in the literature were very high, with IC 50 values ranging from 20 to 60 μM in various solid tumor cell lines [38][39][40]. In agreement with the literature, we found 10 μM ATL had no significant impact on the clonogenic growth of many human cancer cell lines ( Fig.…”

Section: Atl-induced Oxidative Dna Damage Activates Parp In Cancer Cellssupporting

confidence: 89%

Synergistic lethality between PARP-trapping and alantolactone-induced oxidative DNA damage in homologous recombination-proficient cancer cells

et al. 2020

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PARP1 and PARP2 play critical roles in regulating DNA repair and PARP inhibitors have been approved for the treatment of BRCA1/2-mutated ovarian and breast cancers. It has long been known that PARP inhibition sensitizes cancer cells to DNAdamaging cytotoxic agents independent of BRCA status, however, clinical use of PARP inhibitors in combination with DNAdamaging chemotherapy is limited by the more-than-additive cytotoxicity. The natural compound alantolactone (ATL) inhibits the thioredoxin reductase to induce ROS accumulation and oxidative DNA damage selectively in cancer cells. Here, we showed that nontoxic doses of ATL markedly synergized with the PARP inhibitor olaparib to result in synthetic lethality irrespective of homologous recombination status. Synergistic cytotoxicity was seen in cancer but not noncancerous cells and was reduced by the ROS inhibitor NAC or knockdown of OGG1, demonstrating that the cytotoxicity resulted from the repair of ATL-induced oxidative DNA damage. PARP1 knockdown suppressed the synergistic lethality and olaparib was much more toxic than veliparib when combined with ATL, suggesting PARP-trapping as the primary inducer of cytotoxicity. Consistently, combined use of ATL and olaparib caused intense signs of replication stress and formation of double strand DNA breaks, leading to S and G 2 arrest followed by apoptosis. In vivo, the combination effectively induced regression of tumor xenografts, while either agent alone had no effect. Hence, PARP trapping combined with specific pro-oxidative agents may provide safe and effective ways to broaden the therapeutic potential of PARP inhibitors.

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Section: Atl-induced Oxidative Dna Damage Activates Parp In Cancer Cellssupporting

confidence: 89%

Synergistic lethality between PARP-trapping and alantolactone-induced oxidative DNA damage in homologous recombination-proficient cancer cells

et al. 2020

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“…Administration of alantolactone may be capable of inhibiting the Bcl-2/Bax signaling pathway in HeLa cells. Recent studies have suggested that alantolactone likely increases the ratio of Bcl-2 to Bax, therefore inducing apoptosis in cancer cells (33,34).…”

Section: Discussionmentioning

confidence: 99%

Alantolactone induces apoptosis of human cervical cancer cells via reactive oxygen species generation, glutathione depletion and inhibition of the Bcl-2/Bax signaling pathway

Jiang

Wang

2016

Oncology Letters

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Abstract.Alantolactone is the active ingredient in frankincense, and is extracted from the dry root of elecampane. It has a wide variety of uses, including as an insect repellent, antibacterial, antidiuretic, analgesic and anticancer agent. In addition, alantolactone induces apoptosis of human cervical cancer cells, however, its mechanism of action remains to be elucidated. Therefore, the present study investigated whether alantolactone was able to induce apoptosis of human cervical cancer cells, and its potential mechanisms of action were analyzed. Treatment of HeLa cells with alantolactone (0, 10, 20, 30, 40, 50 and 60 µM) for 12 h significantly inhibited growth in a dose-dependent manner. Cells treated with 30 µM of alantolactone for 0, 3, 6 and 12 h demonstrated marked induction of apoptosis in a time-dependent manner. Treatment of HeLa cells with 30 µM of alantolactone for 0, 3, 6 and 12 h significantly induced the generation of reactive oxygen species (ROS) and inhibited glutathione (GSH) production in HeLa cells in a dose-dependent manner. Alantolactone additionally markedly inhibited the Bcl-2/Bax signaling pathway in HeLa cells. Therefore, administration of alantolactone induced apoptosis of human cervical cancer cells via ROS generation, GSH depletion and inhibition of the Bcl-2/Bax signaling pathway.

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“…Cyclin D1 in particular is required at the G1 to S phase. The overexpression of cyclin D1 can release cells from normal cell cycle control and cause a transformation to neoplasia [15,16]. Therefore, the protein level of cyclin D1 was detected by Western blotting.…”

Section: Effects Of β-Carotene On the Cell Cycle And The Expression Omentioning

confidence: 99%

β‐Carotene Induces Apoptosis in Human Esophageal Squamous Cell Carcinoma Cell Lines via the Cav‐1/AKT/NF‐κB Signaling Pathway

Zhu

Zhang

et al. 2016

J Biochem & Molecular Tox

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β-carotene, a type of terpenoid, has many metabolic and physiological functions. In particular, β-carotene has an antitumor effect. However, the efficacy of β-carotene against esophageal squamous cell carcinoma (ESCC) remains unclear. In our study, β-carotene inhibited the growth of ESCC cells and downregulated expression of the Caveolin-1 (Cav-1) protein. Cav-1 protein was expressed only in ESCC cells, not in Het-1A cells. Moreover, β-carotene triggered apoptosis, induced cell cycle G0⁄G1 phase arrest, and inhibited cell migration. To explore the mechanism involved in these processes, we further examined the effect of β-carotene on the Cav-1-mediated AKT/NF-κB pathway. The results showed that the level of AKT and NF-κB phosphorylation was dramatically inhibited, which led to an increase in the Bax/Bcl-2 ratio. Correspondingly, the activity of Caspase-3 was also enhanced. These data suggest that β-carotene has an antiproliferative role in ESCC cells and may be a promising chemotherapeutic agent for use against ESCC cells.

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Alantolactone Induces Apoptosis and Cell Cycle Arrest on Lung Squamous Cancer SK‐MES‐1 Cells

Cited by 35 publications

References 28 publications

Synergistic lethality between PARP-trapping and alantolactone-induced oxidative DNA damage in homologous recombination-proficient cancer cells

Synergistic lethality between PARP-trapping and alantolactone-induced oxidative DNA damage in homologous recombination-proficient cancer cells

Alantolactone induces apoptosis of human cervical cancer cells via reactive oxygen species generation, glutathione depletion and inhibition of the Bcl-2/Bax signaling pathway

β‐Carotene Induces Apoptosis in Human Esophageal Squamous Cell Carcinoma Cell Lines via the Cav‐1/AKT/NF‐κB Signaling Pathway

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