Effect of Doxorubicin/Pluronic SP1049C on Tumorigenicity, Aggressiveness, DNA Methylation and Stem Cell Markers in Murine Leukemia

Abstract

PurposePluronic block copolymers are potent sensitizers of multidrug resistant cancers. SP1049C, a Pluronic-based micellar formulation of doxorubicin (Dox) has completed Phase II clinical trial and demonstrated safety and efficacy in patients with advanced adenocarcinoma of the esophagus and gastroesophageal junction. This study elucidates the ability of SP1049C to deplete cancer stem cells (CSC) and decrease tumorigenicity of cancer cells in vivo.Experimental DesignP388 murine leukemia ascitic tumor was grown in BDF1 mice. The animals were treated with: (a) saline, (b) Pluronics alone, (c) Dox or (d) SP1049C. The ascitic cancer cells were isolated at different passages and examined for 1) in vitro colony formation potential, 2) in vivo tumorigenicity and aggressiveness, 3) development of drug resistance and Wnt signaling activation 4) global DNA methylation profiles, and 5) expression of CSC markers.ResultsSP1049C treatment reduced tumor aggressiveness, in vivo tumor formation frequency and in vitro clonogenic potential of the ascitic cells compared to drug, saline and polymer controls. SP1049C also prevented overexpression of BCRP and activation of Wnt-β-catenin signaling observed with Dox alone. Moreover, SP1049C significantly altered the DNA methylation profiles of the cells. Finally, SP1049C decreased CD133+ P388 cells populations, which displayed CSC-like properties and were more tumorigenic compared to CD133− cells.ConclusionsSP1049C therapy effectively suppresses the tumorigenicity and aggressiveness of P388 cells in a mouse model. This may be due to enhanced activity of SP1049C against CSC and/or altered epigenetic regulation restricting appearance of malignant cancer cell phenotype.

Clinical Translation of Nanomedicine

“…Several preclinical studies have demonstrated improved antitumor efficacy as compared to doxorubicin in mouse models of myeloma and leukemia. 281–283 The drug was found to be well tolerated in a dose-finding phase I study. 284 In this study, 26 patients with tumors refractory to other therapy were treated with escalating doses of SP1049C (5–90 mg/m 2 ).…”

Drug Carriers: Not an Innocent Delivery Man

“…In a phase 2 clinical study in patients with advanced adenocarcinoma of the esophagus and gastroesophageal junction, SP1049C demonstrated appreciable anti-tumor activity as a single agent and an acceptable safety profile (59). SP1049C is currently pursued as an agent targeting cancer stem cells, which are highly tumorigenic and intrinsically drug resistant (55,61).…”

Can nanomedicines kill cancer stem cells?

“…We have shown recently that treatment of the mice bearing the leukemia ascitic cells with SP1049C reduces the tumor aggressiveness, in vivo tumor formation frequency and in vitro clonogenic potential of the leukemia cells derived from the treated animals [252]. SP1049C also prevented the overexpression of BCRP and activation of Wnt/β-catenin signaling observed with doxorubicin alone, significantly altered the DNA methylation profiles of the cells and decreased CD133+ cells populations, which displayed CSCs-like properties and were more tumorigenic compared to CD133− cells [252].…”

“…SP1049C also prevented the overexpression of BCRP and activation of Wnt/β-catenin signaling observed with doxorubicin alone, significantly altered the DNA methylation profiles of the cells and decreased CD133+ cells populations, which displayed CSCs-like properties and were more tumorigenic compared to CD133− cells [252]. Moreover in the same in vivo leukemia ascitic cells model, the treatment of animals with Pluronic P85 and doxorubicin prevented the development of MDR observed upon long-term treatment of the animals with doxorubicin alone [253].…”