Resveratrol Triggers Apoptosis Through Regulating Ceramide Metabolizing Genes in Human K562 Chronic Myeloid Leukemia Cells

Abstract

Resveratrol, an important phytoalexin in many plants, has been reported to have cytotoxic effects on various types of cancer. Ceramide is a bioactive sphingolipid that regulates many signaling pathways, including cell growth and proliferation, senescence and quiescence, apoptosis, and cell cycle. Ceramides are generated by longevity assurance genes (LASS). Glucosylceramide synthase (GCS) and sphingosine kinase-1 (SK-1) enzymes can convert ceramides to antiapoptotic molecules, glucosylceramide, and sphingosine-1-phosphate, respectively. C8:ceramide, an important cell-permeable analogue of natural ceramides, increases intracellular ceramide levels significantly, while 1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) and SK-1 inhibitor increase accumulation of ceramides by inhibiting GCS and SK-1, respectively. Chronic myelogenous leukemia (CML) is a hematological disorder resulting from generation of BCR/ABL oncogene. In this study, we examined the roles of ceramide metabolizing genes in resveratrolinduced apoptosis in K562 CML cells. There were synergistic cytotoxic and apoptotic effects of resveratrol with coadministration of C8:ceramide, PDMP, and SK-1 inhibitor. Interestingly, there were also significant increases in expression levels of LASS genes and decreases in expression levels of GCS and SK-1 in K562 cells in response to resveratrol. Our data, in total, showed for the first time that resveratrol might kill CML cells through increasing intracellular generation and accumulation of apoptotic ceramides.

Major apoptotic mechanisms and genes involved in apoptosis

“…Inhibition of GCS and SK1 triggered apoptosis via leading to ceramide accumulation in imatinibresistant and imatinib-sensitive K562 CML cell lines [209]. Additionally, when we treated K562 human CML cell lines and HL60 human acute pro-myelocytic leukemia cell lines with resveratrol in combination with ceramide analog, GCS inhibitor, or SK1 inhibitor, apoptotic effects of resveratrol increased synergistically in the cells treated with resveratrol and ceramide combination, while the cells treated with resveratrol and GCS or SK1 combinations resisted to apoptosis as compared to the control group [210,211]. Furthermore, our studies also showed that GCS and SK1 inhibition in combination with nilotinib or dasatinib treatment synergistically triggers apoptosis in K562 and Meg01 human CML cell lines [212,213].…”

Resveratrol and quercetin-induced apoptosis of human 232B4 chronic lymphocytic leukemia cells by activation of caspase-3 and cell cycle arrest

“…The apoptosis in SW-872 human liposarcoma cells induced by quercetin was mediated through the activation of caspase-3, Bax, and Bak and then cleavage of PARP and downregulation of Bcl-2. 12 Kim et al showed that antiproliferative effect of quercetin is mediated via inhibition of PI-3 kinase in cancer cells. 24 Our results revealed that resveratrol treatment induced a dose-dependent increase in the percentage of cells in G0/G1 phase, which was accompanied by a corresponding reduction in the percentage of cells in S phase.…”

“…9,10 Resveratrol has been shown to induce apoptosis in a variety of cancers such as chronic myeloid leukemia (CML), acute myeloid leukemia (AML), breast, prostate, colon and lung cancers. [11][12][13] The exact mechanism of resveratrol mediated anticancer effect is not fully identified.…”

“…12,13 It has been also shown that resveratrol inhibits the cell cycle progression by causing arrest at G1/G2 phases. 15 Quercetin, an abundant polyphenol of the flavonoid family, is generated in onions, apples, red grapes, and other fruits and vegetables.…”

Resveratrol-3-O-glucuronide and resveratrol-4′-O-glucuronide reduce DNA strand breakage but not apoptosis in Jurkat T cells treated with camptothecin

“…Resveratrol aglycone has been reported to have anticancer and chemosensitizing activities against cancer cells; mechanisms of action for this have previously been proposed (1,(25)(26)(27)(28). Anticancer mechanisms of action for resveratrol, which have been described predominantly from in vitro studies, include the inhibition of transcription factors, kinases and other molecules involved in cell proliferation and survival.…”