title: Cancer-selective cytotoxic Ca2+ overload in acute myeloid leukemia cells and attenuation of disease progression in mice by synergistically acting polyphenols curcumin and carnosic acid.
abstract: Acute myeloid leukemia (AML) is an aggressive hematologic malignancy characterized by extremely heterogeneous molecular and biologic abnormalities that hamper the development of effective targeted treatment modalities. While AML cells are highly sensitive to cytotoxic Ca2+ overload, the feasibility of Ca2+- targeted therapy of this disease remains unclear. Here, we show that apoptotic response of AML cells to the synergistically acting polyphenols curcumin (CUR) and carnosic acid (CA), combined at low, non-cytotoxic doses of each compound was mediated solely by disruption of cellular Ca2+ homeostasis. Specifically, activation of caspase cascade in CUR+CA-treated AML cells resulted from sustained elevation of cytosolic Ca2+ (Ca2+cyt) and was not preceded by endoplasmic reticulum stress or mitochondrial damage. The CUR+CA-induced Ca2+cyt rise did not involve excessive influx of extracellular Ca2+ but, rather, occurred due to massive Ca2+ release from intracellular stores concomitant with inhibition of Ca2+cyt extrusion through the plasma membrane. Notably, the CUR+CA combination did not alter Ca2+ homeostasis and viability in non-neoplastic hematopoietic cells, suggesting its cancer-selective action. Most importantly, co-administration of CUR and CA to AML-bearing mice markedly attenuated disease progression in two animal models. Collectively, our results provide the mechanistic and translational basis for further characterization of this combination as a prototype of novel Ca2+-targeted pharmacological tools for the treatment of AML.
authors: Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel.
authors: Stella
authors: S
authors: Pesakhov
authors: Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel.
authors: Matan
authors: M
authors: Nachliely
authors: Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel.|Permanent address: Blood Bank Institute, Soroka University Medical Center, Beer Sheva 85025, Israel.
authors: Zeev
authors: Z
authors: Barvish
authors: Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel.|Permanent address: Department of Pathology, Sackler Faculty of Medicine Tel-Aviv University, Tel-Aviv 69978, Israel.
authors: Nasma
authors: N
authors: Aqaqe
authors: Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel.
authors: Bar
authors: B
authors: Schwartzman
authors: The Shraga Segal Department of Microbiology and Immunology, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel.
authors: Elena
authors: E
authors: Voronov
authors: Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel.
authors: Yoav
authors: Y
authors: Sharoni
authors: Department of Pathology and Laboratory Medicine, Rutgers-New Jersey Medical School, Newark, NJ 07103, USA.
authors: George P
authors: GP
authors: Studzinski
authors: Department of Physiology and Cell Biology, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel.
authors: Daniel
authors: D
authors: Fishman
authors: Department of Clinical Biochemistry and Pharmacology, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel.
authors: Michael
authors: M
authors: Danilenko
mesh_terms: D045784:Abietanes / Q000494:pharmacology*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D003474:Curcumin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D018922:HL-60 Cells; D006706:Homeostasis; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D013997:Time Factors; D020298:U937 Cells; D023041:Xenograft Model Antitumor Assays
chemical_list: D045784:Abietanes; D020169:Caspases; D003474:Curcumin; C018381:salvin; D002118:Calcium
keywords: acute myeloid leukemia; apoptosis; carnosic acid; curcumin; intracellular calcium