A Case of Acute Promyelocytic Leukemia during Gefitinib Treatment

Ennishi, Daisuke; Sezaki, Nobuo; Senoo, T; Terui, Yasuhito; Hatake, Kiyohiko; Hino, Norihiko

doi:10.1532/ijh97.06149

Cited by 7 publications

(5 citation statements)

References 7 publications

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“…We first choose erlotinib, a targeted therapy drug and EGFR inhibitor that shows off-target effects in AML leukemia cells and patients. 4 , 5 , 32 – 38 As shown in Figure 7 and consistent with previous reports, erlotinib alone failed to effectively inhibit U937 cell growth. However, in combination with low doses of lapatinib, both drugs showed dramatic growth inhibition of U937 cells.…”

Section: Resultssupporting

confidence: 91%

“… 42 Also, similar to the findings of our study, cytotoxic activity and differentiation induction were found for gefitinib and erlotinib and other targeted therapy drugs against EGFR, in leukemia cells and clinical responses. 4 , 5 , 32 – 38 , 43 According to the previous findings and our preliminary results (data not shown), there are no clear expression patterns for EGFR or ErbB2 in AML or in some of the tested cell lines, such as HL-60, 33 , 36 , 44 , 45 despite the demonstration of a EGF-EGFR autocrine loop in U937 cells. 46 Thus, the real targets of lapatinib, as well as gefitinib and erlotinib EGFR inhibitors need to be further investigated.…”

Section: Discussionmentioning

confidence: 52%

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Lapatinib induces autophagic cell death and differentiation in acute myeloblastic leukemia

Chen

Fang

et al. 2016

OTT

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Lapatinib is an oral-form dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR or ErbB/Her) superfamily members with anticancer activity. In this study, we examined the effects and mechanism of action of lapatinib on several human leukemia cells lines, including acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and acute lymphoblastic leukemia (ALL) cells. We found that lapatinib inhibited the growth of human AML U937, HL-60, NB4, CML KU812, MEG-01, and ALL Jurkat T cells. Among these leukemia cell lines, lapatinib induced apoptosis in HL-60, NB4, and Jurkat cells, but induced nonapoptotic cell death in U937, K562, and MEG-01 cells. Moreover, lapatinib treatment caused autophagic cell death as shown by positive acridine orange staining, the massive formation of vacuoles as seen by electronic microscopy, and the upregulation of LC3-II, ATG5, and ATG7 in AML U937 cells. Furthermore, autophagy inhibitor 3-methyladenine and knockdown of ATG5, ATG7, and Beclin-1 using short hairpin RNA (shRNA) partially rescued lapatinib-induced cell death. In addition, the induction of phagocytosis and ROS production as well as the upregulation of surface markers CD14 and CD68 was detected in lapatinib-treated U937 cells, suggesting the induction of macrophagic differentiation in AML U937 cells by lapatinib. We also noted the synergistic effects of the use of lapatinib and cytotoxic drugs in U937 leukemia cells. These results indicate that lapatinib may have potential for development as a novel antileukemia agent.

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Section: Resultssupporting

confidence: 91%

Section: Discussionmentioning

confidence: 52%

Lapatinib induces autophagic cell death and differentiation in acute myeloblastic leukemia

Chen

Fang

et al. 2016

OTT

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“…Considerable evidence suggests that induction of cytotoxic activity and differentiation occurs with other inhibitors of EGFR, such as gefitinib and erlotinib, in both leukemia cell lines and leukemia patients [37], [38], [39], [40], [41], [42], [43], [44], [45]. Interestingly, one report discussed complete remission in a patient with acute myelogenous leukemia after treatment with erlotinib [46], which resembled the application of all trans retinoic acid (ATRA) for acute promyelocytic leukemia by changing the differentiation status.…”

Section: Discussionmentioning

confidence: 99%

Lapatinib Induces Autophagy, Apoptosis and Megakaryocytic Differentiation in Chronic Myelogenous Leukemia K562 Cells

et al. 2011

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Lapatinib is an oral, small-molecule, dual tyrosine kinase inhibitor of epidermal growth factor receptors (EGFR, or ErbB/Her) in solid tumors. Little is known about the effect of lapatinib on leukemia. Using human chronic myelogenous leukemia (CML) K562 cells as an experimental model, we found that lapatinib simultaneously induced morphological changes resembling apoptosis, autophagy, and megakaryocytic differentiation. Lapatinib-induced apoptosis was accompanied by a decrease in mitochondrial transmembrane potential and was attenuated by the pancaspase inhibitor z-VAD-fmk, indicating a mitochondria-mediated and caspase-dependent pathway. Lapatinib-induced autophagic cell death was verified by LC3-II conversion, and upregulation of Beclin-1. Further, autophagy inhibitor 3-methyladenine as well as autophagy-related proteins Beclin-1 (ATG6), ATG7, and ATG5 shRNA knockdown rescued the cells from lapatinib-induced growth inhibition. A moderate number of lapatinib-treated K562 cells exhibited features of megakaryocytic differentiation. In summary, lapatinib inhibited viability and induced multiple cellular events including apoptosis, autophagic cell death, and megakaryocytic differentiation in human CML K562 cells. This distinct activity of lapatinib against CML cells suggests potential for lapatinib as a therapeutic agent for treatment of CML. Further validation of lapatinib activity in vivo is warranted.

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“…3,4 Contrary to their exciting case presentation, we and others previously observed the emergence of AML-M3 during longterm treatment with gefitinib (250 mg/d), another TKI, in four pa-tients with NSCLC. 5,6 We find these paradoxical clinical results rather interesting.…”

mentioning

confidence: 73%

Paradoxical Clinical Effects of Epidermal Growth Factor Receptor–Tyrosine Kinase Inhibitors for Acute Myelogenous Leukemia

Hotta

Kiura

Takigawa

et al. 2008

JCO

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AML. We consider further research is required to clarify whether TKIs might induce especially the BCR-ABL fusion gene, the genetic cause of AML-M3. 7 We agree with the conclusion of Pitini et al. 1 that TKIs are a potential therapeutic strategy for AML. From this perspective, they shed light on an exciting aspect of EGFR-TKIs that needs to be evaluated in future preclinical and clinical evaluations. In addition, worldwide epidemiological research might clarify the association between long-term TKI treatment and the rare events that we have noted.

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A Case of Acute Promyelocytic Leukemia during Gefitinib Treatment

Cited by 7 publications

References 7 publications

Lapatinib induces autophagic cell death and differentiation in acute myeloblastic leukemia

Lapatinib induces autophagic cell death and differentiation in acute myeloblastic leukemia

Lapatinib Induces Autophagy, Apoptosis and Megakaryocytic Differentiation in Chronic Myelogenous Leukemia K562 Cells

Paradoxical Clinical Effects of Epidermal Growth Factor Receptor–Tyrosine Kinase Inhibitors for Acute Myelogenous Leukemia

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