title: F14512, a polyamine-vectorized anti-cancer drug, currently in clinical trials exhibits a marked preclinical anti-leukemic activity.
abstract: Chemotherapy remains mainly used for the treatment of acute myeloid leukemia (AML). However, in the past 3 decades limited progress has been achieved in improving the long-term disease-free survival. Therefore the development of more effective drugs for AML represents a high level of priority. F14512 combines an epipodophyllotoxin core targeting topoisomerase II with a spermine moiety introduced as a cell delivery vector. The polyamine moiety facilitates F14512 selective uptake by tumour cells via the polyamine transport system, a machinery overactivated in cancer cells. F14512 has been characterized as a potent drug candidate and is currently in Phase I clinical trials. Here, we demonstrated marked survival benefit and therapeutic efficacy of F14512 treatments in a series of human AML models, established either from AML cell lines or from patient AML samples. Furthermore, we reported in vitro synergistic anti-leukemic effects of F14512 in combination with cytosine arabinoside (Ara-C), doxorubicin, gemcitabine, bortezomib or SAHA. In vivo combination of suboptimal doses of F14512 with Ara-C also resulted in enhanced anti-leukemic activity. We further showed that F14512 triggered both senescence and apoptosis in vivo in primary AML models, but not autophagy. Overall, these results support the clinical development in onco-hematology of this novel promising drug candidate.
authors.affiliation: Department of Research, Experimental Oncology Research Center, Pierre Fabre Research Institute, Toulouse, France.
authors.forename: A
authors.initials: A
authors.lastname: Kruczynski
authors.forename: A
authors.initials: A
authors.lastname: Pillon
authors.forename: L
authors.initials: L
authors.lastname: Créancier
authors.forename: I
authors.initials: I
authors.lastname: Vandenberghe
authors.forename: B
authors.initials: B
authors.lastname: Gomes
authors.forename: V
authors.initials: V
authors.lastname: Brel
authors.forename: E
authors.initials: E
authors.lastname: Fournier
authors.forename: J-P
authors.initials: JP
authors.lastname: Annereau
authors.forename: E
authors.initials: E
authors.lastname: Currie
authors.forename: Y
authors.initials: Y
authors.lastname: Guminski
authors.forename: D
authors.initials: D
authors.lastname: Bonnet
authors.forename: C
authors.initials: C
authors.lastname: Bailly
authors.forename: N
authors.initials: N
authors.lastname: Guilbaud
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001897:Boronic Acids / Q000008:administration & dosage; D000069286:Bortezomib; D049109:Cell Proliferation / Q000187:drug effects*; D003561:Cytarabine / Q000008:administration & dosage; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004317:Doxorubicin / Q000008:administration & dosage; D005312:Fetal Blood / Q000166:cytology / Q000187:drug effects*; D005434:Flow Cytometry; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage; D007124:Immunoenzyme Techniques; D053631:Interleukin Receptor Common gamma Subunit / Q000502:physiology*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D011034:Podophyllotoxin / Q000008:administration & dosage / Q000031:analogs & derivatives; D011719:Pyrazines / Q000008:administration & dosage; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D000077337:Vorinostat; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D001897:Boronic Acids; C534191:F14512; D006877:Hydroxamic Acids; C507942:Il2rg protein, mouse; D053631:Interleukin Receptor Common gamma Subunit; D011719:Pyrazines; D012333:RNA, Messenger; D003561:Cytarabine; D003841:Deoxycytidine; D000077337:Vorinostat; D000069286:Bortezomib; D004317:Doxorubicin; D011034:Podophyllotoxin; D000093542:Gemcitabine