G2/M Cell Cycle Arrest and Tumor Selective Apoptosis of Acute Leukemia Cells by a Promising Benzophenone Thiosemicarbazone Compound

Abstract

Anti-mitotic therapies have been considered a hallmark in strategies against abnormally proliferating cells. Focusing on the extensively studied family of thiosemicarbazone (TSC) compounds, we have previously identified 4,4’-dimethoxybenzophenone thiosemicarbazone (T44Bf) as a promising pharmacological compound in a panel of human leukemia cell lines (HL60, U937, KG1a and Jurkat). Present findings indicate that T44Bf-mediated antiproliferative effects are associated with a reversible chronic mitotic arrest caused by defects in chromosome alignment, followed by induced programmed cell death. Furthermore, T44Bf selectively induces apoptosis in leukemia cell lines when compared to normal peripheral blood mononuclear cells. The underlying mechanism of action involves the activation of the mitochondria signaling pathway, with loss of mitochondrial membrane potential and sustained phosphorylation of anti-apoptotic protein Bcl-xL as well as increased Bcl-2 (enhanced phosphorylated fraction) and pro-apoptotic protein Bad levels. In addition, ERK signaling pathway activation was found to be a requisite for T44Bf apoptotic activity. Our findings further describe a novel activity for a benzophenone thiosemicarbazone and propose T44Bf as a promising anti-mitotic prototype to develop chemotherapeutic agents to treat acute leukemia malignancies.

Inhibition of growth of Asian keloid cells with human umbilical cord Wharton’s jelly stem cell-conditioned medium

“…Although AKCs expressed CD29, CD44, CD73, CD90, and CD105 markers [1,34], their expression was significantly reduced in the AKCs after exposure to hWJSC-CM suggesting that AKCs were losing their stemness properties but not in controls. AKCs exposed to hWJSC-CM appear to be inhibited via apoptosis as they were arrested at Sub-G1 and G2/M phases [33], which is the same focal point of cell arrest by other anti-leukemic agents [35]. Furthermore, we observed increased numbers of Annexin-V-positive cells in AKCs exposed to hWJSC-CM compared to controls.…”

Synthesis and antitumor activity of 2‐isocamphanyl thiosemicarbazone derivatives via ROS‐enhanced mitochondrial damage

“…Previously, many studies have demonstrated that thiosemicarbazone derivatives induced mitochondria‐mediated apoptosis in cancer cells (Britta et al., ; Cabrera et al., ; Pessoto et al., ). Moreover, Bcl‐2 family members, caspase‐3, and caspase‐9 are the most important signaling proteins in the mitochondria‐mediated apoptosis pathway.…”

Extracts of Elaeagnus multiflora Thunb. fruit fermented by lactic acid bacteria inhibit SW480 human colon adenocarcinoma via induction of cell cycle arrest and suppression of metastatic potential

“…Upon entry to the S phase, cdk2 associates with cyclin A, which is a protein that is highly involved in the progression in the cell cycle as its level increases steadily until the late G2 phase (Cabrera et al, 2015;Otto & Sicinski, 2017). Meanwhile, the activation of cyclin B-cdc2 complex, also known as the maturation promoting factor (MPF), regulates the transition in the G2/M phase as the activity of the CDK cdc2 is also responsible for governing the entry into the mitosis stage (Baldi et al, 2011;Cabrera et al, 2015;Lu et al, 2005;Zhang et al, 2017) In addition, significant downregulation of cdc25c, which is considered as a mitosis inhibitor, was also elicited by LPLC treatment. Cdc25c is a phosphatase, which prompts the entry into the mitosis phase, thereby inhibiting the arrest at G2/M phase through activation of cdk1(cdc2)/cyclin B complex (Cho, Park et al, 2015;Zhang et al, 2017).…”