Erufosine, a novel alkylphosphocholine, in acute myeloid leukemia: single activity and combination with other antileukemic drugs

Abstract

Purpose Alkylphosphocholines represent a new class of cytostatic drugs with a novel mode of action. Erufosine (ErPC3), the first compound of this class that can be administered intravenously, has recently been shown to be active against human tumor and leukemic cell lines. Methods In order to evaluate the antileukemic potential of ErPC3 in acute myeloid leukemia (AML) the lethal concentration 50% (LC 50) was determined using WST-1 assay. For analysis of cell death, staining for Annexin V and activated caspase 3 was performed. An interaction analysis was performed by calculation of combination index and construction of isobolograms. Results The LC 50 was 7.4 lg/ml after 24 h and 3.2 lg/ ml after 72 h in HL 60 cells and 30.1 and 8.6 lg/ml, respectively, in 19 fresh samples from patients with AML.ErPC3 was found to be cytotoxic in HL60 cells with distinct activation of caspase 3. ErPC3 was not cross-resistant with cytarabine, idarubicine and etoposide as shown by the linear relation of respective LC 50s. The latter agents, however, exerted an additive cytotoxicity in combination with ErPC3 as revealed by isobologram analysis and combination index, although results are uneven for idarubicine. Conclusion Based on these data ErPC3 appears as a novel antileukemic candidate drug, which needs to be explored further in the treatment of AML.

PI3K and Akt as molecular targets for cancer therapy: current clinical outcomes

“…Erufosine, either alone or in combination with other chemotherapeutic agents and ionic radiation, induces apoptosis in different kinds of cancer [141] (Table 3). Erufosine combined with etoposide and cytarabine acts additively in acute myeloid leukemia [142] . Erufosine causes cell death in acute myeloid leukemia by JNK 1/2 activation and ERK 1/2 dephosphorylation, leading to apoptosis [143] .…”

Erucylphosphohomocholine, the first intravenously applicable alkylphosphocholine, is cytotoxic to acute myelogenous leukemia cells through JNK- and PP2A-dependent mechanisms

“…64 In this connection, it is important to emphasize that ErPC3 synergizes in vitro with chemotherapeutic drugs commonly used for treating AML ErPC3-mediated cyotoxicity in AML AM Martelli et al patients. 18 ErPC3 has been studied in a phase I dose escalation trial at the University of Munich. Thereby, plasma steady state levels of 10-20 mM ErPC3 after repeated intravenous application have been reached without showing toxicity (data not shown).…”

“…16,17 Recently, the in vitro cytotoxic effect of ErPC3 in AML cells has been documented. 18 In this study, we have further investigated the mechanisms that could underlay ErPC3 cytotoxicity in AML cells. We demonstrated that ErPC3 activated JNK 1/2.…”

Nanoencapsulação do fármaco miltefosina em micelas poliméricas de poli(óxido de etileno)-poli(óxido de propileno)

“…No entanto, o tratamento antitumoral por via oral com miltefosina é dificuldado pela toxicidade gastrointestinal assim como a administração intravenosa leva a ação hemolítica, o que limita seu uso (LINDNER et al, 2008;FIEGL et al, 2008;SEIFERT et al, 2007;AGRESTA et al, 2003 A grande variação de incidência geográfica nas taxas de câncer de colo do útero reflete diferenças na disponibilidade de triagem, que permite a deteccção e remoção de lessões pré-cancerosas, e prevalência da infecção pelo virus do papiloma (HPV) (VACCARELLA et al, 2013;BRUNI et al, 2010;FORMAN et al, 2012 …”