The flavonoid tangeretin activates the unfolded protein response and synergizes with imatinib in the erythroleukemia cell line K562

Abstract

We explored the mechanism of cell death of the polymethoxyflavone tangeretin (TAN) in K562 breakpoint cluster region-abelson murine leukemia (Bcr-Abl+) cells. Flow cytometric analysis showed that TAN arrested the cells in the G(2)/M phase and stimulated an accumulation of the cells in the sub-G(0) phase. TAN-induced cell death was evidenced by poly(ADP)-ribose polymerase cleavage, DNA laddering fragmentation, activation of the caspase cascade and downregulation of the antiapoptotic proteins Mcl-1 and Bcl-x(L). Pretreatment with the pancaspase inhibitor Z-VAD-FMK_blocked caspase activation and cell cycle arrest but did not inhibit apoptosis which suggest that other cell killing mechanisms like endoplasmic reticulum (ER)-associated cell death pathways could be involved. We demonstrated that TAN-induced apoptosis was preceded by a rapid activation of the proapoptotic arm of the unfolded protein response, namely PKR-like ER kinase. This was accompanied by enhanced levels of glucose-regulated protein of 78 kDa and of spliced X-box binding protein 1. Furthermore, TAN sensitized K562 cells to the cell killing effects of imatinib via an apoptotic mechanism. In conclusion, our results suggest that TAN is able to induce apoptosis in Bcr-Abl+ cells via cell cycle arrest and the induction of the unfolded protein response, and has synergistic cytotoxicity with imatinib.

Multidrug Resistance Reversal and Apoptosis Induction in Human Colon Cancer Cells by Some Flavonoids Present in Citrus Plants

“…The higher cytotoxicity of methylated flavones to cancer cells as compared to their unmethylated counterparts has been reported previously. ,, Naringenin ( 1a ) and aromadendin ( 2 ) were the least cytotoxic compounds, especially to the resistant cells used. This is in agreement with the previous literature, since IC 50 values published for these two flavonoids range from 100 to several hundred μM depending on the cancer cell line used. , In the case of tangeretin ( 3 ) IC 50 values reported in the literature typically aggregate between 20 and 40 μM. ,, …”

“…Tangeretin ( 3 ) was reported previously to induce apoptosis in K562 human erythroleukemia cells, SH-SY5Y human neuroblastoma cells, and HL-60 human promyelocytic leukemia cells but not in MOLT-4 T-lymphocytic leukemia cells, , COLO 205 and HT-29 colorectal carcinoma cells, and MDA-MB-435 and MCF-7 breast cancer cells . Tangeretin-induced cell-cycle G 1 arrest was, however, reported in cancer cell lines in which tangeretin did not induce apoptosis. ,, The decrease of mitochondrial membrane potential, activation of caspases, and DNA fragmentation were identified as the criteria of tangeretin-induced apoptosis attributed to the activation of the intrinsic apoptosis pathway by this flavonoid. Naringenin ( 1a ) is reported to be an effective apoptosis inducer in several cancer cell lines, including HL-60 human promyelocytic leukemia cells, THP-1 human myeloid leukemia cells, and Caco-2 colon cancer cells, in contrast to the present findings in sensitive and resistant colon cancer cells (LoVo and LoVo/Dx).…”

Tangeretin, a citrus polymethoxyflavonoid, induces apoptosis of human gastric cancer AGS cells through extrinsic and intrinsic signaling pathways

“…Tangeretin inhibits the growth of many cell lines such as breast cancer cell lines MDA-MB-435 and MCF-7, human colon cancer cell line HT-29 and leukaemic HL-60 cells through cell cycle arrest or apoptosis (2,7,8). Tangeretin activates the unfolded protein response and synergizes with imatinib in the erythroleukemia cell line K562 and suppresses IL-1β-induced cyclooxygenase (COX)-2 expression through inhibition of p38 MAPK, JNK and AKT activation in human lung carcinoma cells (9,10). In addition, tangeretin was reported to sensitize cisplatinresistant human ovarian cancer cells through downregulation of the phosphoinositide 3-kinase/Akt signaling pathway (11).…”

Inhibition of glycoprotein synthesis in the endoplasmic reticulum as a novel anticancer mechanism of (−)‐epigallocatechin‐3‐gallate

“…The possibility of enhancing the efficacy of chemotherapeutic drugs by the induction or manipulation of ER stress made the ER a promising novel anticancer target [36]. The role of this mechanism in the antitumor activity of some flavanoids has also been recently demonstrated [37, 38]. Accordingly, the antitumor and antiviral effects of certain glucosidase inhibitors, such as DNJ or castanospermine have been extensively studied and approved [39–45].…”