Halogenated boroxine increases propensity to apoptosis in leukemia (UT‐7) but not non‐tumor cells in vitro

Abstract

A hallmark of the development of solid and hematological malignancies is the dysregulation of apoptosis, which leads to an imbalance between cell proliferation, cell survival and death. Halogenated boroxine [K2(B3O3F4OH)] (HB) is a derivative of cyclic anhydride of boronic acid, with reproducible anti‐tumor and anti‐proliferative effects in different cell models. Notably, these changes are observed to be more profound in tumor cells than in normal cells. Here, we investigated the underlying mechanisms through an extensive evaluation of (a) deregulated target genes and (b) their interactions and links with main apoptotic pathway genes upon treatment with an optimized concentration of HB. To provide deeper insights into the mechanism of action of HB, we performed identification, visualization, and pathway association of differentially expressed genes (DEGs) involved in regulation of apoptosis among tumor and non‐tumor cells upon HB treatment. We report that HB at a concentration of 0.2 mg·mL−1 drives tumor cells to apoptosis, whereas non‐tumor cells are not affected. Comparison of DEG profiles, gene interactions and pathway associations suggests that the HB effect and tumor‐‘selectivity’ can be explained by Bax/Bak‐independent mitochondrial depolarization by ROS generation and TRAIL‐like activation, followed by permanent inhibition of NFκB signaling pathway specifically in tumor cells.

New in vitro findings about halogenated boroxine cytotoxicity and deregulation of cell death-related genes in GR-M melanoma cells

“…This kind of rather selective downregulation of BCL-2 expression in GR-M cells is a valuable finding, as the evasion of apoptosis and impaired apoptotic signalling have been crucial for cancer proliferation and resistance to treatment. Our findings support recent reports ( 12 , 19 ) of HB-downregulated BCL-2 protein expression and induction of apoptosis in human leukaemia UT-7 but not normal cells.…”

“…Changes in cell death-related gene expression in GR-M cells confirm our hypothesis that HB would increase melanoma susceptibility to cell death. Our findings corroborate recent in vitro studies reporting evidence of anti-tumour effects of HB in different cancer cell types ( 9 , 11 – 13 , 19 ), including GR-M ( 9 ). Cytotoxic effects were more pronounced against tumour GR-M cells which additionally supports reported selective toxicity of HB ( 11 , 12 , 19 ).…”

“…Our findings corroborate recent in vitro studies reporting evidence of anti-tumour effects of HB in different cancer cell types ( 9 , 11 – 13 , 19 ), including GR-M ( 9 ). Cytotoxic effects were more pronounced against tumour GR-M cells which additionally supports reported selective toxicity of HB ( 11 , 12 , 19 ). However, downregulation of BCL-2 was significant only at 0.4 mg/mL, which suggests that HB concentrations above 0.2 mg/mL induce apoptosis.…”

“…Previous studies of halogenated boroxine (HB) [K 2 (B 3 O 3 F 4 OH)] have shown promising therapeutic effects (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19), especially in view of the fact that cancer cells are more sensitive to HB than normal cells (11,12,19). Several studies reported that HB significantly affected the regulation of apoptosis-related genes in UT-7 human leukaemia (12,19). However, the relative expression of cell deathrelated genes has not been studied yet in human melanoma.…”

Steroid Compounds of Manihot Esculenta Crantz Var. Sao Pedro Petro (Tuber) and Their Cytotoxic Effects on Melanoma Cancer Cells (B16-F10)

“…Apoptosis comprised 2 primary signaling pathways: the extrinsic pathway and the intrinsic pathway. The intrinsic apoptotic pathway was primarily involved in the anticancer effects observed in this study [35][36][37]. One of the signaling of apoptosis was through caspase by activating caspase-9 and caspase-3, where caspase-9 was activated and induced by the apoptosome, then processes downstream caspases, such as caspase-3 to carry out the apoptotic process [38][39][40].…”