Cytotoxicity of apigenin on leukemia cell lines: implications for prevention and therapy

Ruela-de-Sousa, Roberta R.; Fuhler, Gwenny M.; Blom, Nel R.; Ferreira, Carmen Verı́ssima; Aoyama, Hiroshi; Peppelenbosch, Maikel P.

doi:10.1038/cddis.2009.18

Cited by 161 publications

(101 citation statements)

References 35 publications

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“…In contrast, RPMI8226 and U266 cells were blocked in the G0/G1 phase of cell cycle, but showed less induction of apoptosis. These results are reminiscent of a previous study in which treatment of myeloid leukemia cells with the natural compound apigenin resulted in G2/M arrest followed by classic apoptosis, whereas the same compound caused a G0/G1 block in an erythroid leukemia cell line (27), which corresponded to autophagy rather than apoptosis. Autophagy, or autophagocytosis, is a reversible process in which intracellular components are sequestered and degraded in double membrane autophagosomes (28).…”

Section: Discussionsupporting

confidence: 81%

Therapeutic Potential of SH2 Domain-Containing Inositol-5′-Phosphatase 1 (SHIP1) and SHIP2 Inhibition in Cancer

Fuhler

Brooks

Toms

et al. 2011

Mol Med

113

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Many tumors present with increased activation of the phosphatidylinositol 3-kinase (PI3K)-PtdIns(3,4,5)P 3 -protein kinase B (PKB/Akt) signaling pathway. It has long been thought that the lipid phosphatases SH2 domain-containing inositol-5′-phosphatase 1 (SHIP1) and SHIP2 act as tumor suppressors by counteracting with the survival signal induced by this pathway through hydrolysis or PtdIns(3,4,5)P 3 to PtdIns(3,4)P 2 . However, a growing body of evidence suggests that PtdInd(3,4)P 2 is capable of, and essential for, Akt activation, thus suggesting a potential role for SHIP1/2 enzymes as proto-oncogenes. We recently described a novel SHIP1-selective chemical inhibitor (3α-aminocholestane [3AC]) that is capable of killing malignant hematologic cells. In this study, we further investigate the biochemical consequences of 3AC treatment in multiple myeloma (MM) and demonstrate that SHIP1 inhibition arrests MM cell lines in either G0/G1 or G2/M stages of the cell cycle, leading to caspase activation and apoptosis. In addition, we show that in vivo growth of MM cells is blocked by treatment of mice with the SHIP1 inhibitor 3AC. Furthermore, we identify three novel pan-SHIP1/2 inhibitors that efficiently kill MM cells through G2/M arrest, caspase activation and apoptosis induction. Interestingly, in SHIP2-expressing breast cancer cells that lack SHIP1 expression, pan-SHIP1/2 inhibition also reduces viable cell numbers, which can be rescued by addition of exogenous PtdIns(3,4)P 2 . In conclusion, this study shows that inhibition of SHIP1 and SHIP2 may have broad clinical application in the treatment of multiple tumor types.

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Section: Discussionsupporting

confidence: 81%

Therapeutic Potential of SH2 Domain-Containing Inositol-5′-Phosphatase 1 (SHIP1) and SHIP2 Inhibition in Cancer

Fuhler

Brooks

Toms

et al. 2011

Mol Med

113

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“…Apigenin was suggested to elevate the levels of p53, and p53 effector gene expression in these neuroblastoma cells (10). Apigenin also causes cell cycle arrest and sensitizes leukemia cells to vincristine (11). Apigenin has additionally been reported to induce apoptosis of prostate and colon cancer cells through induction of death receptor 5, and to act synergistically with exogenous tumor necrosis factor-related apoptosis-inducing ligand to induce cell apoptosis (12).…”

Section: Introductionmentioning

confidence: 99%

Apigenin enhances the cisplatin cytotoxic effect through p53-modulated apoptosis

Liu

et al. 2016

Oncology Letters

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Abstract. Epidemiological and experimental evidence suggests that dietary flavonoids, including apigenin, have anticancer roles. Apigenin has been reported to elevate p53, a critical molecule in the induction of apoptosis. The present study aimed to investigate whether apigenin, a dietary flavonoid, improves the cytotoxic effect of cisplatin in a cancer cell culture system, and to elucidate the mechanism of this effect. Multiple tumor cell types were treated with apigenin, cisplatin or both drugs. Cell viability was evaluated, and the cytotoxic effect was determined biochemically and microscopically. Treatment with apigenin increased cisplatin-induced DNA damage and the apoptosis of tumor cells in a p53-dependent manner. Apigenin, when used with cisplatin, inhibited cell proliferation and promoted mitogen-activated protein kinase activation and subsequent p53 phosphorylation, leading to p53 accumulation and upregulation of proapoptotic proteins. Cisplatin is one of the most commonly used chemotherapeutic drugs for malignant tumors, but resistance to this drug occurs. The current results therefore demonstrate that dietary flavonoids may diminish the resistance of cancers to cisplatin.

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“…Anti-proliferative and anti-angiogenic property of apigenin has been demonstrated in various cancers including breast (23), cervical (23), lung (24), colon (25), hematologic (26), ovarian (27) and prostate cancer (28). Based on these unique effects of apigenin on various cancers along with its low intrinsic toxicity, apigenin has received great attention as a therapeutic as well as a chemopreventive agent.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of IL-6/STAT3 axis and targeting Axl and Tyro3 receptor tyrosine kinases by apigenin circumvent taxol resistance in ovarian cancer cells

Suh

Lee

et al. 2014

International Journal of Oncology

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Abstract.Ovarian cancer is the number one cause of death from gynaecological malignancy. Platinum-based and taxolbased chemotherapy has been used as a standard therapy, but intrinsic and acquired resistance to chemotherapy is a major obstacle to treat the disease. In the present study, we found that in the chemoresistant ovarian cancer SKOV3/TR cells, interleukin-6 (IL-6), IL-6 receptor and signal transducers and activators of transcription 3 (STAT3) expression as well as STAT3 phosphorylation were upregulated compared to those in parental cells. Silencing of IL-6 using IL-6 siRNA was found to suppress IL-6 production, STAT3 and phospho-STAT3 levels, which eventually reduced proliferation and clonogenicity of taxol-resistant SKOV3/TR cells. In addition, stattic, a STAT3 inhibitor, was found to result in decrease of cell viability and clonogenicity of these cells, indicating that the elevated IL-6 and STAT3, phosphoSTAT3 levels are associated with the development of taxol resistance. Next, we found anti-proliferative effect of apigenin on both SKOV3 and SKOV3/TR cells. RT-PCR and western blot results showed that apigenin significantly reduced the expression of Axl and Tyro3 receptor tyrosine kinases (RTKs) at mRNA and protein level, which account for its cytotoxic activity. We further found that apigenin decreased Akt phosphorylation and the level of B-cell lymphoma-extra large (Bcl-xl or BCL2-like 1 isoform 1), an inhibitor of apoptosis. On the contrary to these results, apigenin had no effect on IL-6 production, STAT3 and phosphoSTAT3 protein levels, suggesting that apigenin exerts its anti-proliferative activity via downregulation of Axl and Tyro3 expression, Akt phosphorylation and Bcl-xl expression, but not modulation of IL-6/STAT3 axis. Taken together, our data suggest that inhibition of IL-6/STAT3 signaling pathway and downregulation of Axl and Tyro3 RTKs expression might be a therapeutic strategy to overcome taxol resistance in ovarian cancer cells. IntroductionOvarian cancer is in the fifth place in respect of cancer-related death in woman (1). Worldwide the annual number of new cases and deaths of ovarian cancer is estimated to be around 0.22 and 0.14 million, respectively (2). Combination of surgery and chemotherapy has been used as a standard therapy for the treatment of ovarian cancer patients, but overall 5-year survival of the patients with stage III and IV still remains at only 20 to 40%. Such poor prognosis of advanced stage ovarian cancer is accounted for by the intrinsic and acquired chemoresistance, since 30% of patients with advanced stages have been reported not to respond to the first-line chemotherapy, paclitaxel and cisplatin/carboplatin, and ~80% of the initial responders eventually relapse and develop chemoresistance (3). However, the underlying molecular mechanisms of chemoresistance in ovarian cancer are not fully understood.The signal transducers and activators of transcription (STAT) family proteins have been reported to be fairly upregulated and constitutively activated in many tum...

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Cytotoxicity of apigenin on leukemia cell lines: implications for prevention and therapy

Cited by 161 publications

References 35 publications

Therapeutic Potential of SH2 Domain-Containing Inositol-5′-Phosphatase 1 (SHIP1) and SHIP2 Inhibition in Cancer

Therapeutic Potential of SH2 Domain-Containing Inositol-5′-Phosphatase 1 (SHIP1) and SHIP2 Inhibition in Cancer

Apigenin enhances the cisplatin cytotoxic effect through p53-modulated apoptosis

Inhibition of IL-6/STAT3 axis and targeting Axl and Tyro3 receptor tyrosine kinases by apigenin circumvent taxol resistance in ovarian cancer cells

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