W941, a new PI3K inhibitor, exhibits preferable anti-proliferative activities against nonsmall cell lung cancer with autophagy inhibitors.
Identifieur interne : 000279 ( Main/Exploration ); précédent : 000278; suivant : 000280W941, a new PI3K inhibitor, exhibits preferable anti-proliferative activities against nonsmall cell lung cancer with autophagy inhibitors.
Auteurs : Dong Liang [République populaire de Chine] ; Hong-Ying Wang [République populaire de Chine] ; Shu Fan [République populaire de Chine] ; Jin Wang [République populaire de Chine] ; Ying Shen [République populaire de Chine] ; Chen-Ying Gao [République populaire de Chine] ; Man-Li Wu [République populaire de Chine] ; She-Min Lu [République populaire de Chine] ; San-Qi Zhang [République populaire de Chine] ; Wei Han [Suède]Source :
- Investigational new drugs [ 1573-0646 ] ; 2019.
Abstract
The PI3K pathway is aberrantly activated in many cancers and plays a critical role in tumour cell proliferation and survival, making it a rational therapeutic target. In the present study, the effects and the underlying mechanism of a new PI3K inhibitor, W941, were investigated in non-small-cell lung cancer (NSCLC). The results of this study showed that W941 inhibited the growth of A549 and Hcc827 cells with IC50 values of 0.12 and 0.23 μM, respectively, and that W941 markedly inhibited the growth of A549 xenograft tumours in a nude mouse model without decreasing body weight. Western blotting assays showed that W941 inhibited the phosphorylation of downstream proteins in the PI3K pathway (AKT, mTOR, p70S6K and 4EBP1) in both A549 and Hcc827 cells. In addition, after W941 treatment, a dose-dependent increase in the ratio of the LC3-II/I ratio was observed. When cells were pre-treated with chloroquine or bafilomycin A1, W941 increased the LC3-II/I ratio, suggesting that W941 acted as an autophagy inducer. Moreover, autophagy blockers enhanced apoptosis after W941 treatment, indicating that W941-induced autophagy actually protected the cells against its cytotoxicity. Our findings suggest that the combination of a PI3K inhibitor with an autophagy inhibitor might be a novel option for NSCLC treatment.
DOI: 10.1007/s10637-019-00886-1
PubMed: 31823159
Affiliations:
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Hong Ying" uniqKey="Wang H" first="Hong-Ying" last="Wang">Hong-Ying Wang</name><affiliation wicri:level="1"><nlm:affiliation>Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, People's Republic of China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061</wicri:regionArea><wicri:noRegion>710061</wicri:noRegion></affiliation></author><author><name sortKey="Fan, Shu" sort="Fan, Shu" uniqKey="Fan S" first="Shu" last="Fan">Shu Fan</name><affiliation wicri:level="1"><nlm:affiliation>Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, People's Republic of China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong 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China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061</wicri:regionArea><wicri:noRegion>710061</wicri:noRegion></affiliation></author><author><name sortKey="Gao, Chen Ying" sort="Gao, Chen Ying" uniqKey="Gao C" first="Chen-Ying" last="Gao">Chen-Ying Gao</name><affiliation wicri:level="1"><nlm:affiliation>School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, People's Republic of China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061</wicri:regionArea><wicri:noRegion>710061</wicri:noRegion></affiliation></author><author><name sortKey="Wu, Man Li" sort="Wu, Man Li" uniqKey="Wu M" first="Man-Li" last="Wu">Man-Li Wu</name><affiliation wicri:level="1"><nlm:affiliation>School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, People's Republic of China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061</wicri:regionArea><wicri:noRegion>710061</wicri:noRegion></affiliation></author><author><name sortKey="Lu, She Min" sort="Lu, She Min" uniqKey="Lu S" first="She-Min" last="Lu">She-Min Lu</name><affiliation wicri:level="1"><nlm:affiliation>School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, People's Republic of China.</nlm:affiliation><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 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wei.han@ki.se.</nlm:affiliation><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Women's and Children's Health, Solna, Karolinska Institutet, Karolinska University Hospital, 17176, Stockholm</wicri:regionArea><placeName><settlement type="city">Stockholm</settlement><region nuts="2">Svealand</region></placeName></affiliation></author></analytic><series><title level="j">Investigational new drugs</title><idno type="eISSN">1573-0646</idno><imprint><date when="2019" type="published">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The PI3K pathway is aberrantly activated in many cancers and plays a critical role in tumour cell proliferation and survival, making it a rational therapeutic target. In the present study, the effects and the underlying mechanism of a new PI3K inhibitor, W941, were investigated in non-small-cell lung cancer (NSCLC). The results of this study showed that W941 inhibited the growth of A549 and Hcc827 cells with IC<sub>50</sub> values of 0.12 and 0.23 μM, respectively, and that W941 markedly inhibited the growth of A549 xenograft tumours in a nude mouse model without decreasing body weight. Western blotting assays showed that W941 inhibited the phosphorylation of downstream proteins in the PI3K pathway (AKT, mTOR, p70S6K and 4EBP1) in both A549 and Hcc827 cells. In addition, after W941 treatment, a dose-dependent increase in the ratio of the LC3-II/I ratio was observed. When cells were pre-treated with chloroquine or bafilomycin A1, W941 increased the LC3-II/I ratio, suggesting that W941 acted as an autophagy inducer. Moreover, autophagy blockers enhanced apoptosis after W941 treatment, indicating that W941-induced autophagy actually protected the cells against its cytotoxicity. Our findings suggest that the combination of a PI3K inhibitor with an autophagy inhibitor might be a novel option for NSCLC treatment.</div></front></TEI><affiliations><list><country><li>République populaire de Chine</li><li>Suède</li></country><region><li>Svealand</li></region><settlement><li>Stockholm</li></settlement></list><tree><country name="République populaire de Chine"><noRegion><name sortKey="Liang, Dong" sort="Liang, Dong" uniqKey="Liang D" first="Dong" last="Liang">Dong Liang</name></noRegion><name sortKey="Fan, Shu" sort="Fan, Shu" uniqKey="Fan S" first="Shu" last="Fan">Shu Fan</name><name sortKey="Gao, Chen Ying" sort="Gao, Chen Ying" uniqKey="Gao C" first="Chen-Ying" last="Gao">Chen-Ying Gao</name><name sortKey="Lu, She Min" sort="Lu, She Min" uniqKey="Lu S" first="She-Min" last="Lu">She-Min Lu</name><name sortKey="Shen, Ying" sort="Shen, Ying" uniqKey="Shen Y" first="Ying" last="Shen">Ying Shen</name><name sortKey="Wang, Hong Ying" sort="Wang, Hong Ying" uniqKey="Wang H" first="Hong-Ying" last="Wang">Hong-Ying Wang</name><name sortKey="Wang, Jin" sort="Wang, Jin" uniqKey="Wang J" first="Jin" last="Wang">Jin Wang</name><name sortKey="Wu, Man Li" sort="Wu, Man Li" uniqKey="Wu M" first="Man-Li" last="Wu">Man-Li Wu</name><name sortKey="Zhang, San Qi" sort="Zhang, San Qi" uniqKey="Zhang S" first="San-Qi" last="Zhang">San-Qi Zhang</name></country><country name="Suède"><region name="Svealand"><name sortKey="Han, Wei" sort="Han, Wei" uniqKey="Han W" first="Wei" last="Han">Wei Han</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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