Cytotoxicity, DNA damage, and apoptosis induced by titanium dioxide nanoparticles in human non-small cell lung cancer A549 cells

Background: Cassane-type diterpenoids are widely distributed in the medical plants of genus Caesalpinia. To date, plenty of cassane diterpenoids have been isolated from the genus Caesalpinia, and some of them were documented to exhibit multiple biological activities. However, the effects of these compounds on autophagy have never been reported. Objective: To investigate the effects and mechanisms of the cassane diterpenoids including Phanginin R (PR) on autophagy in Non-Small Cell Lung Cancer (NSCLC) A549 cells. Methods: Western blot analysis and immunofluorescence assay were performed to investigate the effects of the compounds on autophagic flux in A549 cells. The pathway inhibitor and siRNA interference were used to investigate the mechanism of PR. MTT assay was performed to detect cell viability. Results: PR treatment upregulated the expression of phosphatidylethanolamine-modified microtubule-associated protein Light-Chain 3 (LC3-II) in A549 cells. Immunofluorescence assay showed that PR treatment increased the production of red-fluorescent puncta in mRFP-GFP-LC3 plasmid-transfected cells, indicating PR promoted autophagic flux in A549 cells. PR treatment activated the c-Jun N-terminal Kinase (JNK) signaling pathway while it did not affect the classical Akt/mammalian Target of Rapamycin (mTOR) pathway. Pretreatment with the JNK inhibitor SP600125 or siRNA targeting JNK or c-Jun suppressed PR-induced autophagy. In addition, cotreatment with the autophagy inhibitor Chloroquine (CQ) or inhibition of the JNK/c-Jun signaling pathway increased PR-induced cytotoxicity. Conclusion: PR induced cytoprotective autophagy in NSCLC A549 cells via the JNK/c-Jun signaling pathway, and autophagy inhibition could further improve the anti-cancer potential of PR.

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Small-molecule inhibition of APE1 induces apoptosis, pyroptosis, and necroptosis in non-small cell lung cancer

Cell Death and Disease ◽

10.1038/s41419-021-03804-7 ◽

2021 ◽

Vol 12 (6) ◽

Author(s):

Kaili Long ◽

Lili Gu ◽

Lulu Li ◽

Ziyu Zhang ◽

Enjie Li ◽

...

Keyword(s):

Lung Cancer ◽

Dna Damage ◽

Small Cell Lung Cancer ◽

Cell Lines ◽

Small Molecule ◽

Cell Lung Cancer ◽

Small Cell ◽

Nsclc Cell ◽

Molecular Compound ◽

Small Cell Lung

AbstractApurinic/apyrimidinic endonuclease 1 (APE1) plays a critical role in the base excision repair (BER) pathway, which is responsible for the excision of apurinic sites (AP sites). In non-small cell lung cancer (NSCLC), APE1 is highly expressed and associated with poor patient prognosis. The suppression of APE1 could lead to the accumulation of unrepaired DNA damage in cells. Therefore, APE1 is viewed as an important marker of malignant tumors and could serve as a potent target for the development of antitumor drugs. In this study, we performed a high-throughput virtual screening of a small-molecule library using the three-dimensional structure of APE1 protein. Using the AP site cleavage assay and a cell survival assay, we identified a small molecular compound, NO.0449-0145, to act as an APE1 inhibitor. Treatment with NO.0449-0145 induced DNA damage, apoptosis, pyroptosis, and necroptosis in the NSCLC cell lines A549 and NCI-H460. This inhibitor was also able to impede cancer progression in an NCI-H460 mouse model. Moreover, NO.0449-0145 overcame both cisplatin- and erlotinib-resistance in NSCLC cell lines. These findings underscore the importance of APE1 as a therapeutic target in NSCLC and offer a paradigm for the development of small-molecule drugs that target key DNA repair proteins for the treatment of NSCLC and other cancers.

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A Small Compound KJ-28d Enhances the Sensitivity of Non-Small Cell Lung Cancer to Radio- and Chemotherapy

International Journal of Molecular Sciences ◽

10.3390/ijms20236026 ◽

2019 ◽

Vol 20 (23) ◽

pp. 6026

Author(s):

Hwani Ryu ◽

Hyo Jeong Kim ◽

Jie-Young Song ◽

Sang-Gu Hwang ◽

Jae-Sung Kim ◽

...

Keyword(s):

Lung Cancer ◽

Dna Damage ◽

Ionizing Radiation ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Therapeutic Agent ◽

Apoptotic Cell ◽

Combined Treatment ◽

Small Cell ◽

Small Cell Lung

We previously reported on a poly (ADP-ribose) polymerase (PARP) 1/2 inhibitor N-(3-(hydroxycarbamoyl)phenyl)carboxamide (designated KJ-28d), which increased the death of human ovarian cancer BRCA1-deficient SNU-251 cells. In the present study, we further investigated the antitumor activities of KJ-28d in BRCA-proficient non-small cell lung cancer (NSCLC) cells to expand the use of PARP inhibitors. KJ-28d significantly inhibited the growth of NSCLC cells in vitro and in vivo, and induced DNA damage and reactive oxygen species in A549 and H1299 cells. Combined treatment with KJ-28d and ionizing radiation led to increased DNA damage responses in A549 and H1299 cells compared to KJ-28d or ionizing radiation alone, resulting in apoptotic cell death. Moreover, the combination of KJ-28d plus a DNA-damaging therapeutic agent (carboplatin, cisplatin, paclitaxel, or doxorubicin) synergistically inhibited cell proliferation, compared to either drug alone. Taken together, the findings demonstrate the potential of KJ-28d as an effective anti-cancer therapeutic agent for BRCA-deficient and -proficient cancer cells. KJ-28d might have potential as an adjuvant when used in combination with radiotherapy or DNA-damaging agents, pending further investigations.

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ISOLIQUIRITIGENIN INHIBITS THE PROLIFERATION AND INDUCES THE APOPTOSIS OF HUMAN NON-SMALL CELL LUNG CANCER A549 CELLS

Clinical and Experimental Pharmacology and Physiology ◽

10.1111/j.1440-1681.2004.04016.x ◽

2004 ◽

Vol 31 (7) ◽

pp. 414-418 ◽

Cited By ~ 51

Author(s):

Ya-Ling Hsu ◽

Po-Lin Kuo ◽

Lien-Chai Chiang ◽

Chun-Ching Lin

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

A549 Cells ◽

Small Cell ◽

Small Cell Lung

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Combination of baicalein and docetaxel additively inhibits the growth of non-small cell lung cancer in vivo

Traditional Medicine and Modern Medicine ◽

10.1142/s2575900018500131 ◽

2018 ◽

Vol 01 (03) ◽

pp. 213-218 ◽

Cited By ~ 1

Author(s):

Linwei Lu ◽

Zhengxiao Zhao ◽

Lumei Liu ◽

Weiyi Gong ◽

Jingcheng Dong

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

A549 Cells ◽

Small Cell ◽

Small Cell Lung ◽

Tumor Bearing ◽

Liver And Kidney ◽

To Receive

Objective: The objective of this study is to preliminarily evaluate the efficacy of the combination of baicalein and docetaxel on non-small cell lung cancer (NSCLC) in vivo. Methods: The subcutaneous model was established by inoculation of A549 cells, and then these tumor-bearing mice were randomly assigned to eight groups to receive normal saline (NS) as control, baicalein alone, Taxotere[Formula: see text] (docetaxel injection) alone or the combination of baicalein and Taxotere[Formula: see text]. The effect of the combination treatment was evaluated by [Formula: see text] value. Tumors were harvested for TUNEL and CD31 immunohistochemical staining and important organs for H&E staining. Results: Baicalein 50[Formula: see text]mg/kg plus docetaxel 10[Formula: see text]mg/kg significantly reduced tumor weight and inhibited the growth rate of tumor, displaying the additive effect indicated by the [Formula: see text] value. Increased apoptosis and decreased tumor angiogenesis also provided pathological evidence. Additionally, baicalein 50[Formula: see text]mg/kg plus docetaxel 10[Formula: see text]mg/kg did not increase toxicity in lung, liver and kidney. Conclusion: Baicalein 50[Formula: see text]mg/kg plus docetaxel 10[Formula: see text]mg/kg additively inhibits the growth of NSCLC in vivo, and the mechanism underlying remains to be discovered.

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DNA-Damage Inducible 1 is a Property of Human Non-Small Cell Lung Cancer

Tuberculosis and Respiratory Diseases ◽

10.4046/trd.2012.72.2.124 ◽

2012 ◽

Vol 72 (2) ◽

pp. 124

Author(s):

Ji Yeon Lee ◽

Eunsil Kang ◽

Beom Jin Lim ◽

Yoon Soo Chang ◽

Se-Kyu Kim

Keyword(s):

Lung Cancer ◽

Dna Damage ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Small Cell ◽

Small Cell Lung

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Kinesin superfamily protein 21B acts as an oncogene in non-small cell lung cancer

10.21203/rs.3.rs-20245/v2 ◽

2020 ◽

Author(s):

Zhi-Gang Sun ◽

Feng Pan ◽

Jing-Bo Shao ◽

Qian-Qian Yan ◽

Lu Lu ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Nude Mice ◽

Cell Lung Cancer ◽

A549 Cells ◽

Small Cell ◽

Normal Lung ◽

Migration And Invasion ◽

Small Cell Lung ◽

Kinesin Superfamily

Abstract Background: Kinesin superfamily proteins (KIFs) serve as microtubule-dependent molecular motors, and are involved in the progression of many malignant tumors. In this study, we aimed to investigate the expression pattern and precise role of kinesin family member 21B (KIF21B) in non-small cell lung cancer (NSCLC). Methods: KIF21B expression in 72 cases of NSCLC tissues was measured by immunohistochemical staining (IHC). We used shRNA-KIF21B interference to silence KIF21B in NSCLC H1299 and A549 cells and normal lung epithelial bronchus BEAS-2B cells. The biological roles of KIF21B in the growth and metastasis abilities of NSCLC cells were measured by Cell Counting Kit-8 (CCK8), colony formation and Hoechst 33342/PI, wound-healing, and Transwell assays, respectively. Expression of apoptosis-related proteins was determined using western blot. The effect of KIF21B on tumor growth in vivo was examined using nude mice model. Results: KIF21B was up-regulated in NSCLC tissues, and correlated with pathological lymph node and pTNM stage, its high expression was predicted a poor prognosis of patients with NSCLC. Silencing of KIF21B mediated by lentivirus-delivered shRNA significantly inhibited the proliferation ability of H1299 and A549 cells. KIF21B knockdown increased apoptosis in H1299 and A549 cells, down-regulated the expression of Bcl-2 and up-regulated the expression of Bax and active Caspase 3. Moreover, KIF21B knockdown decreased the level of phosphorylated form of Akt (p-Akt) and Cyclin D1 expression in H1299 and A549 cells. In addition, silencing of KIF21B impeded the migration and invasion of H1299 and A549 cells. Further, silencing of KIF 21B dramatically inhibited xenograft growth in BALB/c nude mice. However, silencing of KIF21B did not affect the proliferation, migration and invasion of BEAS-2B cells.Conclusions: These results reveal that KIF21B is up-regulated in NSCLC and acts as an oncogene in the growth and metastasis of NSCLC, which may function as a potential therapeutic target and a prognostic biomarker for NSCLC.

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