title: Rationale and efficacy of proteasome inhibitor combined with arsenic trioxide in the treatment of acute promyelocytic leukemia.
abstract: Arsenic trioxide (ATO) mediates PML-RARA (promyelocytic leukemia-retinoic acid receptor-α) oncoprotein degradation via the proteasome pathway and this degradation appears to be critical for achieving cure in acute promyeloytic leukemia (APL). We have previously demonstrated significant micro-environment-mediated drug resistance (EMDR) to ATO in APL. Here we demonstrate that this EMDR could be effectively overcome by combining a proteasome inhibitor (bortezomib) with ATO. A synergistic effect on combining these two agents in vitro was noted in both ATO-sensitive and ATO-resistant APL cell lines. The mechanism of this synergy involved downregulation of the nuclear factor-κB pathway, increase in unfolded protein response (UPR) and an increase in reactive oxygen species generation in the malignant cell. We also noted that PML-RARA oncoprotein is effectively cleared with this combination in spite of proteasome inhibition by bortezomib, and that this clearance is mediated through a p62-dependent autophagy pathway. We further demonstrated that proteasome inhibition along with ATO had an additive effect in inducing autophagy. The beneficial effect of this combination was further validated in an animal model and in an on-going clinical trial. This study raises the potential of a non-myelotoxic proteasome inhibitor replacing anthracyclines in the management of high-risk and relapsed APL.
authors: Department of Haematology, Christian Medical College, Vellore, India.
authors: S
authors: S
authors: Ganesan
authors: Department of Haematology, Christian Medical College, Vellore, India.
authors: A A
authors: AA
authors: Alex
authors: Department of Haematology, Christian Medical College, Vellore, India.
authors: E
authors: 0000-0001-7032-9301
authors: E
authors: Chendamarai
authors: Department of Haematology, Christian Medical College, Vellore, India.
authors: N
authors: N
authors: Balasundaram
authors: Department of Haematology, Christian Medical College, Vellore, India.
authors: H K
authors: HK
authors: Palani
authors: Department of Haematology, Christian Medical College, Vellore, India.
authors: S
authors: S
authors: David
authors: Department of Haematology, Christian Medical College, Vellore, India.
authors: U
authors: U
authors: Kulkarni
authors: Genotypic Technology, Bengaluru, India.
authors: M
authors: M
authors: Aiyaz
authors: Genotypic Technology, Bengaluru, India.
authors: R
authors: R
authors: Mugasimangalam
authors: Department of Haematology, Christian Medical College, Vellore, India.
authors: A
authors: A
authors: Korula
authors: Department of Haematology, Christian Medical College, Vellore, India.
authors: A
authors: A
authors: Abraham
authors: Department of Haematology, Christian Medical College, Vellore, India.
authors: A
authors: A
authors: Srivastava
authors: UMR-S1131, Hôpital Saint Louis, Paris, France.|Institut Universitaire d' Hématologie, Universite Paris Diderot, Paris, France.
authors: R A
authors: RA
authors: Padua
authors: UMR-S1131, Hôpital Saint Louis, Paris, France.|Institut Universitaire d' Hématologie, Universite Paris Diderot, Paris, France.
authors: C
authors: C
authors: Chomienne
authors: Department of Haematology, Christian Medical College, Vellore, India.
authors: B
authors: B
authors: George
authors: Department of Haematology, Christian Medical College, Vellore, India.
authors: P
authors: P
authors: Balasubramanian
authors: Department of Haematology, Christian Medical College, Vellore, India.
authors: V
authors: V
authors: Mathews
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000627:therapeutic use*; D001343:Autophagy / Q000187:drug effects; D000069286:Bortezomib / Q000627:therapeutic use; D045744:Cell Line, Tumor; D017690:Cell Transplantation; D004357:Drug Synergism; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D016328:NF-kappa B / Q000187:drug effects; D010087:Oxides / Q000627:therapeutic use*; D061988:Proteasome Inhibitors / Q000627:therapeutic use*; D017382:Reactive Oxygen Species / Q000819:agonists; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D056811:Unfolded Protein Response / Q000187:drug effects
chemical_list: D001152:Arsenicals; D016328:NF-kappa B; D010087:Oxides; D061988:Proteasome Inhibitors; D017382:Reactive Oxygen Species; D000069286:Bortezomib; D000077237:Arsenic Trioxide