Multi-kinase inhibitors interact with sildenafil and ERBB1/2/4 inhibitors to kill tumor cells in vitro and in vivo.
Multi-kinase inhibitors interact with sildenafil and ERBB1/2/4 inhibitors to kill tumor cells in vitro and in vivo.
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DOI：
10.18632/oncotarget.9752
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发表时间：
2016-06-28
期刊：
影响因子：
--
通讯作者：
Dent P
中科院分区：
文献类型：
--
作者：
Booth L;Albers T;Roberts JL;Tavallai M;Poklepovic A;Lebedyeva IO;Dent P
我们最近已经证明，多激酶抑制剂，如索拉非尼和帕唑帕尼可以抑制检测分子伴侣的原位免疫荧光，这是进一步增强磷酸二酯酶5抑制剂。索拉非尼和帕唑帕尼抑制HSP 90 ATP酶活性，IC 50值分别约为1.0 μM和75 nM。帕唑帕尼以两种可能的姿势通过计算机对接到HSP 90 ATP结合口袋中。帕唑帕尼和西地那非联合使用可降低HSP 1H/p105和c-MYC的总蛋白水平，并减少它们的共定位。索拉非尼/帕唑帕尼与西地那非以[GRP 78 + HSP 27]依赖性方式联合：（i）深度激活eIF 2 α/Beclin 1通路;（ii）深度激活mTOR并增加ATG 13磷酸化，共同导致毒性自噬体的形成。在NSCLC的新鲜PDX分离株中，联合敲除[ERBB 1 + ERBB 3]或使用ERBB 1/2/4抑制剂阿法替尼改变了细胞形态，增强了ATG 13磷酸化，灭活了NFκB，并进一步增强了[索拉非尼B/帕唑帕尼B+西地那非]致死性。敲低PI 3 K p110α/β或使用buparlisib、copanlisib或特异性p110α抑制剂BYL 719获得了与阿法替尼相同的数据。阿法替尼适应性NSCLC克隆对buparlisib或copanlisib耐药，但对[索拉非尼+西地那非]或[帕唑帕尼+西地那非]比对照克隆更敏感。拉帕替尼显著增强了[瑞格非尼+西地那非]的体内抗肿瘤作用;阿法替尼和BYL 719分别增强了[索拉非尼+西地那非]和[帕唑帕尼]的体内抗肿瘤作用。
We have recently demonstrated that multi-kinase inhibitors such as sorafenib and pazopanib can suppress the detection of chaperones by in situ immuno-fluorescence, which is further enhanced by phosphodiesterase 5 inhibitors. Sorafenib and pazopanib inhibited the HSP90 ATPase activity with IC50 values of ~1.0 μM and ~75 nM, respectively. Pazopanib docked in silico with two possible poses into the HSP90 ATP binding pocket. Pazopanib and sildenafil combined to reduce the total protein levels of HSP1H/p105 and c-MYC and to reduce their co-localization. Sorafenib/pazopanib combined with sildenafil in a [GRP78+HSP27] –dependent fashion to: (i) profoundly activate an eIF2α/Beclin1 pathway; (ii) profoundly inactivate mTOR and increase ATG13 phosphorylation, collectively resulting in the formation of toxic autophagosomes. In a fresh PDX isolate of NSCLC combined knock down of [ERBB1+ERBB3] or use of the ERBB1/2/4 inhibitor afatinib altered cell morphology, enhanced ATG13 phosphorylation, inactivated NFκB, and further enhanced [sorafenib/pazopanib + sildenafil] lethality. Identical data to that with afatinib were obtained knocking down PI3K p110α/β or using buparlisib, copanlisib or the specific p110α inhibitor BYL719. Afatinib adapted NSCLC clones were resistant to buparlisib or copanlisib but were more sensitive than control clones to [sorafenib + sildenafil] or [pazopanib + sildenafil]. Lapatinib significantly enhanced the anti-tumor effect of [regorafenib + sildenafil] in vivo; afatinib and BYL719 enhanced the anti-tumor effects of [sorafenib + sildenafil] and [pazopanib] in vivo, respectively.
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影响因子：
--
作者：
Booth L;Roberts JL;Tavallai M;Webb T;Leon D;Chen J;McGuire WP;Poklepovic A;Dent P
通讯作者：
Dent P
影响因子：
5.6
作者：
Roberts JL;Tavallai M;Nourbakhsh A;Fidanza A;Cruz-Luna T;Smith E;Siembida P;Plamondon P;Cycon KA;Doern CD;Booth L;Dent P
通讯作者：
Dent P
影响因子：
5.6
作者：
Booth L;Roberts JL;Tavallai M;Nourbakhsh A;Chuckalovcak J;Carter J;Poklepovic A;Dent P
通讯作者：
Dent P
影响因子：
3.3
作者：
Qiao, L;Studer, E;Dent, P
通讯作者：
Dent, P
影响因子：
20.3
作者：
Zappasodi, Roberta;Ruggiero, Giusi;Di Nicola, Massimo
通讯作者：
Di Nicola, Massimo