Arsenic trioxide and mannitol for the treatment of acute promyelocytic leukemia relapse in the central nervous system Approximately 3% to 5% of patients with acute promyelocytic leukemia (APL) will have an extramedullary relapse in their lifetimes, most commonly in the central nervous system (CNS).1 CNS relapse can be isolated or associated with a bone marrow (BM) relapse. The most appropriate clinical management remains controversial. 2 The major obstacle to all treatments is the need for the therapeutic drugs to penetrate the blood-brain barrier (BBB). Although arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) are among the frontline medications for APL intramarrow treatment, these water-soluble medicines have limited ability to cross the BBB and cannot reach therapeutically effective levels in the cerbrospinal fluid (CSF). With regular oral doses, the ATO level in CSF has been reported to reach only 17.7% of the corresponding levels in plasma. 3 Previously, we investigated the potential efficacy of combination therapy with mannitol and ATO using a rabbit model, and we showed that the approach caused a transient increase in the BBB permeability for ATO, thereby increasing the ATO concentration in CSF. 4 Our experiments using human cortical neurons revealed a differential tolerance of APL blasts to different concentrations of ATO. 5,6 We also identified a safe range of ATO concentrations in the human CNS. 7,8The results from these collective studies allowed an ATO concentration in CSF that was both safe and therapeutic to be achieved. Here, we describe our efforts to extend the application of our method to additional patients. This study was registered at www.isrctn.org (#ISRCTN94954912). The study protocol was reviewed and approved by the Harbin Medical University Medical Ethics Committee, and signed informed consent was obtained from all patients or their legal guardians. Seventeen CNS APL patients diagnosed between 2000 and 2010 were included in this study (10 males and 7 females, between 6 and 50 years old). Expression of the PML/RARa gene [or t(15;17)(q22;q21) transcripts] was detected in all patient CSF. For all patients, the induction treatment was started immediately on diagnosis. The daily protocol was as follows: a bolus infusion of 125 mL of 20% mannitol mixed in 100 mL normal saline (NS) (for children #15 years old: 50 mL mannitol and 50 mL NS) was administered intravenously at a flow rate of 12 ;20 mL/min (;8-11 minutes total), followed by a slow intravenous infusion of 125 mL of 20% mannitol plus 7.0 mg/m 2 /day ATO (for children #15 years: 50 mL mannitol and 0.16 mg/kg/day ATO) in 500 mL NS at a flow rate of 1.0 mL/min (;9-10.5 hours total). Patients were instructed to rest in bed during the entire procedure. Urine flow was measured to ensure maintenance of a rate of at least 30 to 50 mL/h. Daily infusions were continued until the patient's CSF was found to be free of APL blasts/ promyelocytes. The level of elemental arsenic metabolites was measured in each patient's CSF and blood s...
Background Acute lymphoblastic leukemia (ALL) is an aggressive hematopoietic malignancy that is most commonly observed in children. Alantolactone (ALT) has been reported to exhibit anti-tumor activity in different types of cancer. The aim of the present study was to investigate the anti-tumor activity and molecular mechanism of ALT in ALL. Methods ALL cell lines were treated with 1, 5 and 10 μM ALT, and cell viability was assessed using an MTT assay and RNA sequencing. Flow cytometry, JC-1 staining and immunofluorescence staining assays were used to measure cell apoptosis and autophagy. Additionally, western blot analysis was used to detect expression of apoptosis and autophagy related proteins. Finally, the effects of ALT on tumor growth were assessed in a BV173 xenograft nude mouse model. Results ALT inhibited the proliferation of ALL cells in a dose-dependent manner. Additionally, it was demonstrated that ALT inhibited cell proliferation, colony formation, autophagy, induced apoptosis and reduced tumor growth in vivo through upregulating the expression of adaptor related protein complex 2 subunit mu 1 (AP2M1). Moreover, the autophagy activator rapamycin, attenuated the pro-apoptotic effects of ALT on BV173 and NALM6 cell lines. Overexpression of AP2M1 decreased the expression of Beclin1 and the LC3-II/LC3-1 ratio, and increased p62 expression. Knockdown of Beclin1 increased the levels of bax, cleaved caspase 3 and cytochrome C, and decreased bcl-2 expression. Conclusions The present study demonstrated that ALT exerts anti-tumor activity through inducing apoptosis and inhibiting autophagy by upregulating AP2M1 in ALL, highlighting a potential therapeutic strategy for treatment of ALL.
Background: Acute lymphoblastic leukemia (ALL) is an aggressive hematopoietic malignancy that is most commonly observed in children. Alantolactone (ALT) has been reported to exhibit anti-tumor activity in different types of cancer. The aim of the present study was to investigate the anti-tumor activity and molecular mechanism of ALT in ALL. Methods: ALL cell lines were treated with 1, 5 and 10 μM ALT, and cell viability was assessed using an MTT assay and RNA sequencing. Flow cytometry, JC-1 staining and immunofluorescence staining assays were used to measure cell apoptosis and autophagy. Additionally, western blot analysis was used to detect expression of apoptosis and autophagy related proteins. Finally, the effects of ALT on tumor growth were assessed in a BV173 xenograft nude mouse model. Results: ALT inhibited the proliferation of ALL cells in a dose-dependent manner. Additionally, it was demonstrated that ALT inhibited cell proliferation, colony formation, autophagy, induced apoptosis and reduced tumor growth in vivo through upregulating the expression of adaptor related protein complex 2 subunit mu 1 (AP2M1). Moreover, the autophagy activator rapamycin, attenuated the pro-apoptotic effects of ALT on BV173 and NALM6 cell lines. Overexpression of AP2M1 decreased the expression of Beclin1 and the LC3-II/LC3-1 ratio, and increased p62 expression. Knockdown of Beclin1 increased the levels of bax, cleaved caspase 3 and cytochrome C, and decreased bcl-2 expression. Conclusions: The present study demonstrated that ALT exerts anti-tumor activity through inducing apoptosis and inhibiting autophagy by upregulating AP2M1 in ALL, highlighting a potential therapeutic strategy for treatment of ALL.
Background: Acute lymphoblastic leukemia (ALL) is an aggressive hematopoietic malignancy and most commonly seen in children. Alantolactone (ATL) has been reported to have anti-tumor activities in different types of cancer. This study aimed to evaluate the anti-tumor activity and molecular mechanisms of ATL in ALL. Methods: The ALL cells were treated with 1, 5 and 10μM of of ALT, and then subjected to MTT assay and RNA sequencing. Flow cytometry, JC-1 staining and immunofluorescence staining assay were employed to measure cell apoptosis and autophagy. Meanwhile, western blot analysis was used to detect apoptosis and autophagy-related proteins. Finally, the effect of ALT on tumor growth was measured in BV173 xenograft nude mouse model. Results: In this study, we demonstrated that ALT could inhibit the proliferation of ALL cells by inducing apoptosis and inhibiting autophagy. Administration of rapamycin activated autophagy while reversing the effect of ALT on apoptosis. Mechanically, ALT could induce apoptosis and inhibit autophagy by promoting AM2P1 expression. Further, AM2P1 was figured to inhibit beclin1 phosphorylation so that the apartment between beclin1 and bcl-2 was alleviated to participate in the regulation of autophagy and apoptosis in ALL cell. Conclusions: This study disclosed that Alantolactone can inhibit cell autophagy and promote apoptosis through targeting AP2M1 in acute lymphotic leukemia, indicating a potential therapeutic strategy for ALLtreatment.
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