Abstract
2-Hydroxypropyl-β-cyclodextrin (HPβCD) is a Food and Drug Administration-approved excipient used to improve the stability and bioavailability of drugs. Despite its wide use as a drug delivery vehicle and the recent approval of a clinical trial to evaluate its potential for the treatment of a cholesterol storage disorder, the cellular pathways involved in the adaptive response that is activated upon exposure to HPβCD are still poorly defined. Here, we show that cell treatment with HPβCD results in the activation of the transcription factor EB, a master regulator of lysosomal function and autophagy, and in enhancement of the cellular autophagic clearance capacity. HPβCD administration promotes transcription factor EB-mediated clearance of proteolipid aggregates that accumulate due to inefficient activity of the lysosome-autophagy system in cells derived from a patient with a lysosomal storage disorder. Interestingly, HPβCD-mediated activation of autophagy was found not to be associated with activation of apoptotic pathways. This study provides a mechanistic understanding of the cellular response to HPβCD treatment, which will inform the development of safe HPβCD-based therapeutic modalities and may enable engineering HPβCD as a platform technology to reduce the accumulation of lysosomal storage material.
Highlights
The drug delivery vehicle 2-hydroxypropyl--cyclodextrin (HPCD) prevents cholesterol storage
We found that activation of autophagy observed upon HPCD administration, under conditions that result in activation of transcription factor EB (TFEB) and clearance of autophagic material, is not associated with activation of apoptosis
As observed for genes involved in lysosomal function, MAPLC3B and BECN1 were found to be up-regulated in late infantile neuronal ceroid lipofuscinosis (LINCL) fibroblasts treated with HPCD and control small interfering RNAs (siRNA) (2.4- and 3.2-fold; p Ͻ 0.01, respectively), down-regulated in cells treated with TFEB siRNA (0.5fold; p Ͻ 0.01), and up-regulated in cells treated with TFEB siRNA and HPCD (1.6- and 1.3-fold; p Ͻ 0.01, respectively) compared with cells treated with control siRNA (Fig. 5C)
Summary
The drug delivery vehicle 2-hydroxypropyl--cyclodextrin (HPCD) prevents cholesterol storage. We show that cell treatment with HPCD results in the activation of the transcription factor EB, a master regulator of lysosomal function and autophagy, and in enhancement of the cellular autophagic clearance capacity. TFEB activation was shown to lower the accumulation of ceroid lipopigments in fibroblasts derived from a patient with juvenile NCL [43], suggesting a potential role of TFEB as a therapeutic target for the treatment of NCLs. Because of the similarities between the biological effects of HPCD administration and TFEB activation, including the ability to activate autophagy and promote cellular clearance, we hypothesized that TFEB mediates activation of autophagy observed upon HPCD administration. These findings unveil the molecular pathway involved in the cellular response to HPCD treatment and establish HPCD as a platform technology to develop nanotherapeutics for the treatment of diseases characterized by accumulation of lysosomal storage material
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