Identification of amentoflavone as a potent highly selective PARP-1 inhibitor and its potentiation on carboplatin in human non-small cell lung cancer

Hu, Xiaolong; Feng, Jiahao; Pham, Thi-Anh; Ma, Haiyan; Ma, Mingquan; Song, Rui; Shen, Wei; Xiong, Fei; Zhang, Xiaoqi; Ye, Wen‐Cai; Wang, Hao

doi:10.1016/j.phymed.2018.09.012

Cited by 30 publications

(22 citation statements)

References 32 publications

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“…Since we initially identified KJ-28d as a PARPi, further studies need to be conducted to elucidate other modes of action, as they may be cytotoxic. Platinum-based agents are widely used for a broad range of solid tumors, including NSCLC, and are the most commonly studied combination partners of PARPi [26,31,38]. Likewise, our results demonstrated that KJ-28d significantly enhanced the sensitivity of A549 and H1299 cells to carboplatin or cisplatin.…”

Section: Discussionsupporting

confidence: 68%

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

Ryu

Kim

Song

et al. 2019

IJMS

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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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Section: Discussionsupporting

confidence: 68%

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

Ryu

Kim

Song

et al. 2019

IJMS

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“…Apoptosis is one of the most important anticancer mechanisms (32). Many chemotherapeutic compounds, like DDP (26) and CBP (33), have been found to inhibit tumor growth by inducing apoptosis. With DAPI staining, we observed condensation and margination of chromatin in the A549 cells that were treated with LBP for 24 h. In the FCM analysis, the LBP-induced apoptosis rates were found to be dose- and time-dependent.…”

Section: Discussionmentioning

confidence: 99%

Lobaplatin-Induced Apoptosis Requires p53-Mediated p38MAPK Activation Through ROS Generation in Non-Small-Cell Lung Cancer

et al. 2019

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Platinum-based chemotherapy is recommended as the first-line treatment regimen for patients with advanced non-small-cell lung cancer (NSCLC). Lobaplatin (LBP), a third-generation platinum anti-neoplastic agent, has shown an improved efficacy. This study is aimed to investigate the mechanisms of LBP-induced apoptosis in the A549 p53 wild-type cell line. The Cell Counting Kit-8 assay (CCK-8), flow cytometry (FCM), Western blot, xenograft tumor models, terminal deoxynucleotide transferase dUTP nick end labeling (TUNEL), and RNA interference were used in this study. Our results showed that the proliferation of A549 cells could be inhibited by LBP. At lower concentrations, LBP triggered cell cycle arrest at the G1 phase in A549 cells. LBP could also induce apoptosis of A549 cells. LBP also increased the expression of PARP and Bax and the cleavage of caspase-3, caspase-8, and caspase-9 and reduced Bcl-2 expression. In vivo experiment confirmed that LBP could inhibit tumor growth in the A549 xenograft models and induce apoptosis. Apoptosis of A549 cells was decreased after transfected with p53 shRNA or treated with reactive oxygen species inhibitor NAC and p38MAPK inhibitor SB203580, suggesting that the p53/ROS/p38MAPK pathway appeared to mediate the LBP-induced apoptosis of A549 cells. Our data demonstrate that LBP could be a promising candidate for the treatment of NSCLC with wild-type p53.

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“…More recently, the anticancer activities of AF have been associated with downregulation of Skp2 in ovarian cancer (Liu et al, ). Hu et al () found that AF can be a potent PARP‐1 inhibitor with a high specificity and a candidate adjuvant agent to boost the anticancer effect of carboplatin in NSCLC. In present study, our results indicated that AF suppressed NSCLC in vitro and in vivo , which was associated with induction of apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Retracted: Amentoflavone Promotes Apoptosis in Non‐Small‐Cell Lung Cancer by Modulating Cancerous Inhibitor of PP2A

Shen

Chen

et al. 2019

The Anatomical Record

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Non‐small‐cell lung cancer (NSCLC) is one of the most common human malignancies. Amentoflavone (AF) is one of bioflavonoid compounds isolated from Selaginella tamariscina Spring. This study was designed to examine the effect of AF on NSCLC. Our results indicated that AF decreased cell viability of both H1299 and H358 cells. Colony formation assay also showed that AF was able to suppress the anchorage‐independent growth of NSCLC cells. AF also triggered cell cycle arrest by downregulating cyclin D1, CDK4, and CDK6. The pro‐apoptotic activity of AF was confirmed by Hoechst staining and flow cytometry. The effect of AF on activation of caspase‐3, upregulation of Bax, and downregulation of Bcl‐2 was examined by western blot. The anti‐growth and pro‐apoptotic activities of AF were further validated in xenograft murine model. iTRAQ assay showed that cancerous inhibitor of PP2A (CIP2A) expression was markedly downregulated by AF treatment in H1299 cells. In addition, qRT‐PCR and western blot also showed that AF was able to dose‐dependently inhibit CIP2A expression. Meanwhile, the activity of protein phosphatase 2A (PP2A) was enhanced by AF treatment. The mRNA and protein expression of CIP2A as well as PP2A activity in xenograft tumor tissue were examined, which indicated that the in vivo anticancer activity of AF was associated with downregulation of CIP2A and reactivation of PP2A. Moreover, our results showed that the anti‐growth and pro‐apoptotic activities of AF were augmented by CIP2A knockdown and attenuated by ectopic CIP2A expression. Our results indicated that AF exhibited anticancer activity in NSCLC by targeting CIP2A. Anat Rec, 302:2201–2210, 2019. © 2019 American Association for Anatomy

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Identification of amentoflavone as a potent highly selective PARP-1 inhibitor and its potentiation on carboplatin in human non-small cell lung cancer

Cited by 30 publications

References 32 publications

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

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

Lobaplatin-Induced Apoptosis Requires p53-Mediated p38MAPK Activation Through ROS Generation in Non-Small-Cell Lung Cancer

Retracted: Amentoflavone Promotes Apoptosis in Non‐Small‐Cell Lung Cancer by Modulating Cancerous Inhibitor of PP2A

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