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.

Cancer‐Specific Therapy by Artificial Modulation of Intracellular Calcium Concentration

“…The Ca 2+ homeostasis of cancer cells is governed by a network composed of various Ca 2+ channels and transporters . In general, transient elevation of cytosolic Ca 2+ was favorable for cancer cells proliferation and survival while apoptosis is usually triggered by long‐term cytosolic Ca 2+ rise . The low cytosolic Ca 2+ concentration, which serves as the baseline as well as medium for Ca 2+ signaling, is maintained by a complicated Ca 2+ transport system…”

Prophylactic and curative effect of rosemary leaves extract in a bleomycin model of pulmonary fibrosis

“…2008 ) and curcumin (Pesakhov et al. 2016 ). It is, thus, very plausible that carnosic acid cooperated with other phenol compounds in our rosemary extract, rosmarinic acid, for example, to boost its antifibrotic and antioxidant activities.…”

The Natural Occurring Compounds Targeting Endoplasmic Reticulum Stress

“…Results also indicate that intracellular Ca 2+ mobilization is required but not sufficient for inducing AML apoptosis. However, ER stress and mitochondrial damage are not involved in this mechanical regulation [ 88 ]. Calreticulin, a Ca 2+ -binding protein, acts as a multifunctional chaperone located in ER and plays a critical role in cancer cell growth and peritoneal dissemination.…”