Anti-leukemic activity of betulinic acid from bulk to self-assembled structure

Abstract

The Ziziphus jujuba tree is one of the major sources of betulinic acid (BA). After isolation, the bulk structure of the compound was converted to a self-assembled nanofibers (SA-BA) configuration which showed better anti-leukemic efficacy than its bulk form. After internalization in leukemic cells, SA-BA elevated reactive oxygen species (ROS) and pro-inflammatory cytokine secretion which ultimately activated apoptosis pathway. The SA-BA showed potent ameliorative role against acute chemotherapeutic toxicity induced by doxorubicin in human peripheral blood lymphocytes through the mechanism totally opposite to said pathway. Thus, SA-BA showed cell specific distinct effects. It was also revealed that the SA-BA had potent immunomodulatory affected on T cells and macrophages by polarizing the cytokine balance toward Th1 at a slightly higher dose. SA-BA arrested the growth of in vivo cancer by increasing the CD4 + cells in associated with increased cytotoxic T-cell response. SA-BA was also selectively internalized in folate receptor overexpressing leukemic cells. For this purpose, folic acid (FA) and polyethylene glycol (PEG) were conjugated on the nanostructured of SA-BA. After internalization, the conjugate (FA-PEG-SA-BA) diminished the cellular redox system and generated an excess amount of ROS which induced tumor necrosis factor-alpha-mediated cell death through activation of caspase 8 and 3 cascade system. Throughout all these studies, no toxic effects of the conjugates toward normal cells were observed. Thus, the whole study enlightens the multifunctional role of SA-BA in different aspects of anti-leukemic therapy which may be useful in future treatment policies.

Keywords

• Anti-leukemic
• betulinic acid
• drug delivery
• folate receptor
• immunomodulation
• self-assembled