title: Combination of Rad001 (everolimus) and propachlor synergistically induces apoptosis through enhanced autophagy in prostate cancer cells.
abstract: PI3K/AKT/mTOR pathway plays a key role in the tumorigenesis of many human cancers including prostate cancer. However, inhibitors of this pathway, such as Rad001, have not shown therapeutic efficacy as a single agent. Through a high-throughput screen of 5,000 widely used small molecules, we identified compounds that can synergize with Rad001 to inhibit prostate cancer cells. One of the compounds, propachlor, synergizes with Rad001 to induce apoptosis of castration-resistant prostate cancer cells via enhanced autophagy. This enhanced autophagic cell death is accompanied by increased Beclin1 expression as well as upregulation of Atg5-Atg12 conjugate and LC3-2. Rad001 and propachlor can also synergistically inhibit tumors in a xenograft animal model of prostate cancer. These findings provide a novel direction to develop combination therapies for advanced and metastatic prostate cancer that has failed the currently available therapies.
authors.affiliation: Department of Urology and Anhui Geriatric Institute, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Tai
authors.forename: Yin
authors.initials: Y
authors.lastname: Sun
authors.forename: Nan
authors.initials: N
authors.lastname: Liu
authors.forename: Boxiao
authors.initials: B
authors.lastname: Ding
authors.forename: Elaine
authors.initials: E
authors.lastname: Hsia
authors.forename: Sunita
authors.initials: S
authors.lastname: Bhuta
authors.forename: Ryan K
authors.initials: RK
authors.lastname: Thor
authors.forename: Robert
authors.initials: R
authors.lastname: Damoiseaux
authors.forename: Chaozhao
authors.initials: C
authors.lastname: Liang
authors.forename: Jiaoti
authors.initials: J
authors.lastname: Huang
mesh_terms: D000083:Acetanilides / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001343:Autophagy; D000071192:Autophagy-Related Protein 12; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; D045744:Cell Line, Tumor; D004357:Drug Synergism; D000068338:Everolimus; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D025841:Small Ubiquitin-Related Modifier Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C466624:ATG12 protein, human; C502778:ATG5 protein, human; D000083:Acetanilides; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D000071192:Autophagy-Related Protein 12; D000071187:Autophagy-Related Protein 5; C491997:BECN1 protein, human; D000071186:Beclin-1; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D025841:Small Ubiquitin-Related Modifier Proteins; C011088:propachlor; D000068338:Everolimus; D020123:Sirolimus