Involvement of Autophagy in Antitumor Activity of Folate-appended Methyl-β-cyclodextrin

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Abstract
Autophagy, the major lysosomal pathway for recycling intracellular components including organelles, is emerging as a key process regulating tumorigenesis and cancer therapy. Most recently, we newly synthesized folate-appended methyl-[bgr]-cyclodextrin (FA-M-[bgr]-CyD), and demonstrated the potential of FA-M-[bgr]-CyD as a new antitumor drug. In this study, we investigated whether anticancer activity of FA-M-[bgr]-CyD in folate receptor-[agr] (FR-[agr])-positive tumor cells is involved in autophagy. In contrast to methyl-[bgr]-cyclodextrin (M-[bgr]-CyD), FA-M-[bgr]-CyD entered KB cells (FR-[agr] (+)) through CLIC/GEEC endocytosis. No significant depression in the DNA content was observed in KB cells after treatment with FA-M-[bgr]-CyD. Additionally, the transmembrane potential of mitochondria after treatment with FA-M-[bgr]-CyD was drastically elevated. Meanwhile, FA-M-[bgr]-CyD induced the formation of autophagic vacuoles, which were partially colocalized with mitochondria, in KB cells. Taken together, these results suggest that FR-[agr]-expressing cell-selective cytotoxic activity of FA-M-[bgr]-CyD could be mediated by the regulation of autophagy, rather than the induction of apoptosis.

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