title: Akt and p53 are potential mediators of reduced mammary tumor growth by cloroquine and the mTOR inhibitor RAD001.
abstract: PI3K/Akt/mTOR and p53 signaling pathways are frequently deregulated in tumors. The anticancer drug RAD001 (everolimus) is a known mTOR-inhibitor, but mTOR-inhibition leads to phosphorylation of Akt inducing resistance against RAD001 treatment. There is growing evidence that conflicting signals transduced by the oncogene Akt and the tumorsuppressor p53 are integrated via negative feedback between the two pathways. We previously showed that the anti-malarial Chloroquine, a 4-alkylamino substituted quinoline, is a p53 activator and reduced the incidence of breast tumors in animal models. Additionally, Chloroquine is an effective chemosensitizer when used in combination with PI3K/Akt inhibitors but the mechanism is unknown. Therefore, our aim was to test, if Chloroquine could inhibit tumor growth and prevent RAD001-induced Akt activation. Chloroquine and RAD001 caused G1 cell cycle arrest in luminal MCF7 but not in mesenchymal MDA-MB-231 breast cancer cells, they significantly reduced MCF7 cell proliferation on a collagen matrix and mammospheroid formation. In a murine MCF7 xenograft model, combined treatment of Chloroquine and RAD001 significantly reduced mammary tumor growth by 4.6-fold (p = 0.0002) compared to controls. Chloroquine and RAD001 inhibited phosphorylation of mTOR and its downstream target, S6K1. Furthermore, Chloroquine was able to block the RAD001-induced phosphorylation of Akt serine 473. The Chloroquine effect of overcoming the RAD001-induced activation of the oncogene Akt, as well as the promising antitumor activity in our mammary tumor animal model present Chloroquine as an interesting combination partner for the mTOR-inhibitor RAD001.
authors.affiliation: Department of Obstetrics and Gynecology, University Hospital Erlangen, Universitaetsstr. 21-23, 91054 Erlangen, Germany. christian.loehberg@uk-erlangen.de
authors.forename: Christian R
authors.initials: CR
authors.lastname: Loehberg
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Strissel
authors.forename: Ralf
authors.initials: R
authors.lastname: Dittrich
authors.forename: Reiner
authors.initials: R
authors.lastname: Strick
authors.forename: Juergen
authors.initials: J
authors.lastname: Dittmer
authors.forename: Angela
authors.initials: A
authors.lastname: Dittmer
authors.forename: Ben
authors.initials: B
authors.lastname: Fabry
authors.forename: Willi A
authors.initials: WA
authors.lastname: Kalender
authors.forename: Thorsten
authors.initials: T
authors.lastname: Koch
authors.forename: David L
authors.initials: DL
authors.lastname: Wachter
authors.forename: Nicole
authors.initials: N
authors.lastname: Groh
authors.forename: Astrid
authors.initials: A
authors.lastname: Polier
authors.forename: Ina
authors.initials: I
authors.lastname: Brandt
authors.forename: Laura
authors.initials: L
authors.lastname: Lotz
authors.forename: Inge
authors.initials: I
authors.lastname: Hoffmann
authors.forename: Florentine
authors.initials: F
authors.lastname: Koppitz
authors.forename: Sonja
authors.initials: S
authors.lastname: Oeser
authors.forename: Andreas
authors.initials: A
authors.lastname: Mueller
authors.forename: Peter A
authors.initials: PA
authors.lastname: Fasching
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lux
authors.forename: Matthias W
authors.initials: MW
authors.lastname: Beckmann
authors.forename: Michael G
authors.initials: MG
authors.lastname: Schrauder
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology*; D000068338:Everolimus; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D051058:Oncogene Protein v-akt / Q000235:genetics / Q000378:metabolism*; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D016159:Tumor Suppressor Protein p53; D002738:Chloroquine; D000068338:Everolimus; D051058:Oncogene Protein v-akt; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus