title: The dual mTORC1 and mTORC2 inhibitor PP242 shows strong antitumor activity in a pheochromocytoma PC12 cell tumor model.
abstract: OBJECTIVE
  To assess the activity of mTOR and downstream effector proteins in the mTOR pathway after treatment with a dual mTOR complex 1 and 2 (mTORC1/2) inhibitor (PP242) compared with that of mTOR complex 1 (mTORC1) inhibitor (rapamycin) using a xenograft tumor model.
  
  
  METHODS
  Pheochromocytoma PC12 cell were xenografted into nude mice. Animals were treated with PP242 and rapamycin. Mean tumor volume was compared across groups. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining was used to detect apoptosis. Immunoblot analysis was performed to assess mTORC1/2 activity using p-Akt, p-S6, and p-4E-BP1. The expression of the antiapoptotic protein Bcl-2, pro-apoptotic protein Bax, and the mediator of angiogenesis vascular endothelial growth factor were also investigated.
  
  
  RESULTS
  The mean tumor volume of PP242 was significantly lower than in other groups. The terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling results showed that PP242 markedly increased cell apoptosis compared with other groups. Immunoblot analysis of tumor lysates treated with PP242 demonstrated inhibition of activated p-Akt. We also observed that only PP242, but not rapamycin, significantly reduced Bcl-2 expression and markedly increased Bax expression. Rapamycin decreased vascular endothelial growth factor expression, but not nearly as striking as seen in the PP242 group.
  
  
  CONCLUSIONS
  Our study showed that PP242 showed strong antitumor activity in a pheochromocytoma PC12 cell tumor model. Based on our study, dual mTORC1/2 kinase inhibitors warrant further investigation as a potential treatment for malignant pheochromocytomas or paragangliomas.
authors.affiliation: Department of Urology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Urology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Xianjin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Urology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Qin
authors.affiliation: Department of Urology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Tianyuan
authors.initials: T
authors.lastname: Xu
authors.affiliation: Department of Urology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Zhaowei
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: Department of Urology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Shan
authors.initials: S
authors.lastname: Zhong
authors.affiliation: Department of Urology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Minguang
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Urology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China. Electronic address: zxh340@yeah.net.
authors.forename: Zhoujun
authors.initials: Z
authors.lastname: Shen
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000188:drug therapy*; D000818:Animals; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use*; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008807:Mice, Inbred BALB C; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors*; D016716:PC12 Cells; D010673:Pheochromocytoma / Q000188:drug therapy*; D011687:Purines / Q000494:pharmacology* / Q000627:therapeutic use*; D051381:Rats; D020123:Sirolimus / Q000494:pharmacology* / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: D007211:Indoles; D046912:Multiprotein Complexes; D011687:Purines; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases; C572919:PP242; D020123:Sirolimus