Aldehyde biphenyl chalcones induce immunogenic apoptotic-like cell death and are promising new safe compounds against a wide range of hematologic cancers

Aim: Investigate the apoptotic mechanisms of two new aldehyde biphenyl chalcones on leukemia cells. Materials & methods: From a series of 71 new chalcones, we selected the two most cytotoxic. Results: JA3 and JA7 were cytotoxic not only against hematological malignancies but also against solid tumor and cancer stem cells, yet with no toxicity to normal cells. Moreover, they induced immunogenic apoptotic-like cell death independently of promyelocytic leukemia protein, with extensive mitochondrial damages downstream of endoplasmic reticulum stress. Preventing endoplasmic reticulum stress and the upregulation of proapoptotic machinery inhibited JA3- and JA7-induced cell death. Likewise, blocking receptor Fas protected cells from killing. They increased the antileukemic effect of cytarabine and vincristine and killed leukemic cells collected from patients with different acute leukemia subtypes. Conclusion: JA3 and JA7 represent new promising prototypes for the development of new chemotherapeutics.

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Programmed cell death proteins and chronic leukemia

Archives of Biological Sciences ◽

10.2298/abs1103527b ◽

2011 ◽

Vol 63 (3) ◽

pp. 527-535

Author(s):

G. Brajuskovic ◽

Milica Strnad ◽

Snezana Cerovic ◽

Stanka Romac

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Leukemic Cells ◽

Leukemia Cells ◽

Chronic Leukemia ◽

Morphological Aspects ◽

Pathological Conditions ◽

Wide Range ◽

Induction Of Apoptosis ◽

Apoptotic Genes

Apoptosis or programmed cell death is a genetically regulated process of cellular suicide. Apoptosis has been implicated in a wide range of pathological conditions, and mutations in apoptotic genes play important roles in the process of malignant transformation. Chronic leukemia represents a neoplastic disorder caused primarily by defective programmed cell death, as opposed to increased cell proliferation. This paper presents the main results of our ten-year research on the apoptosis of leukemia cells. The research included the morphological aspects of the process, the effect of antineoplastic agents on the induction of apoptosis in leukemia cells and expression analysis of the proteins involved in programmed cell death. Special attention was paid to the expression and interaction of the Bcl-2 family of proteins in leukemia cells. The ultimate aim of the study of apoptosis of leukemic cells is the discovery of new biological agents that might be used in the treatment of chronic leukemia.

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Honokiol induces paraptosis-like cell death of acute promyelocytic leukemia via mTOR & MAPK signaling pathways activation

APOPTOSIS ◽

10.1007/s10495-020-01655-9 ◽

2021 ◽

Author(s):

Xiaoli Liu ◽

Yan Gu ◽

Yaoyao Bian ◽

Danhong Cai ◽

Yu Li ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Cell Death ◽

Endoplasmic Reticulum Stress ◽

Signaling Pathway ◽

Acute Promyelocytic Leukemia ◽

Mapk Signaling ◽

Promyelocytic Leukemia ◽

Protein Synthesis Inhibitor ◽

Protein Accumulation ◽

Nb4 Cells

AbstractAcute promyelocytic leukemia (APL) is a blood system disease caused by the accumulation of a large number of immature blood cells in bone marrow. Although the introduction of all-trans retinoic acid (ATRA) and arsenic has reached a high level of complete remission rate and 5-year disease-free survival rate, the occurrence of various adverse reactions still severely affects the quality of life of patients. As a natural product, honokiol (HNK) has the advantages of low toxicity and high efficiency, and it is a potential drug for the treatment of cancer. Since cancer cells can escape apoptotic cell death through multiple adaptive mechanisms, HNK, a drug that induces cancer cell death in a nonapoptotic way, has attracted much interest. We found that HNK reduced the viability of human APL cell line (NB4 cells) by inducing paraptosis-like cell death. The process was accompanied by excessive reactive oxygen species (ROS), mitochondrial damage, endoplasmic reticulum stress, and increased microtubule-associated protein 1 light chain 3 (LC3) processing. The inactivation of proteasome activity was the main cause of misfolded and unfolded protein accumulation in endoplasmic reticulum, such as LC3II/I and p62. This phenomenon could be alleviated by adding cycloheximide (CHX), a protein synthesis inhibitor. We found that mTOR signaling pathway participated in paraptosis-like cell death induced by HNK in an autophagy-independent process. Moreover, the mitogen-activated protein kinase (MAPK) signaling pathway induced paraptosis of NB4 cells by promoting endoplasmic reticulum stress. In summary, these findings indicate that paraptosis may be a new way to treat APL, and provide novel insights into the potential mechanism of paraptosis-like cell death.

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