2-Hydroxypropyl-β-cyclodextrin (HPβCD) as a Potential Therapeutic Agent for Breast Cancer

Abstract

Cholesterol accumulation is documented in various malignancies including breast cancer. Consequently, depleting cholesterol in cancer cells can serve as a viable treatment strategy. We identified the potency of 2-hydroxypropyl-β-cyclodextrin (HPβCD), a cholesterol-depletor in vitro against two breast cancer cell lines: MCF-7 (Oestrogen-receptor positive, ER+) and MDA-MB-231 (Triple negative breast cancer (TNBC)). The results were then compared against two non-cancerous cell lines using cytotoxic-, apoptosis-, and cholesterol-based assays. Treatment with HPβCD showed preferential and significant cytotoxic potential in cancer cells, inducing apoptosis in both cancer cell lines (p < 0.001). This was mediated due to significant depletion of cholesterol (p < 0.001). We further tested HPβCD in a MF-1 mice (n = 14) xenograft model and obtained 73.9%, 94% and 100% reduction in tumour size for late-, intermediate-, and early-stage TNBC, respectively. We also detected molecular-level perturbations in the expression patterns of several genes linked to breast cancer and cholesterol signalling pathways using RT2-PCR arrays and have identified SFRP1 as a direct binding partner to HPβCD through SPR drug interaction analysis. This work unravels mechanistic insights into HPβCD-induced cholesterol depletion, which leads to intrinsic apoptosis induction. Results from this study potentiate employing cholesterol depletion as a promising unconventional anticancer therapeutic strategy, which warrants future clinical investigations.

Rescuing a Troubled Tolcapone with PEGylated PLGA Nanoparticles: Design, Characterization, and Hepatotoxicity Evaluation

“…As suggested by other authors, HPβCD can reduce ROS production via cholesterol depletion in oxidative stress-induced cells. 39,40 As tolcapone showed to induce lipid accumulation in hepatic cells by promoting hepatocellular triglyceride accumulation in another study, we hypothesize that HPβCD might have a role in lipid metabolism, protecting the cells from impairments caused by drugs. 13 For the moment, and to the best of our knowledge, the exact mechanisms of how HPβCD, and cyclodextrin, in general, protects cells remain elusive.…”

“…Indeed other works have pointed out that HPβCD can reduce ROS production via cholesterol depletion in oxidative stress-induced cells, thus exhibiting antioxidant and anticytotoxic properties. 39,40 The PLGA-GAL@Tolc formulation was unable to reduce ROS production in both media, except for the formulation tested at 50 μM in glucose medium (Figure 7a), where ROS production was increased. These results suggest that HPβCD might have a dual function in the formulation: cryoprotection of NPs and an anticytotoxic effect, protecting cells from tolcapone ROSinduced aggression.…”

“…So, there is the possibility that tolcapone and HPβCD form a complex after tolcapone's release from PLGA NPs, protecting cells from tolcapone's aggression. So, despite that the same concentrations are tested in cellular studies with free and encapsulated drug, the rate of internalization in cells seems not to be the same; (3) as indicated above, it is possible that HPβCD has a dual role in this formulation as a cryoprotectant and antioxidant agent, which was in fact already described by Saha et al 39 It was noticed that both PLGA-HP and PLGA-HP@Tolc displayed a decrease in ROS production after 24 h of exposure in both mediums tested. Furthermore, when we verified the cell viability of HepG2 cells after exposure to free tolcapone with HPβCD (Figure S5), it was observed a decrease of cell viability when compared with PLGA-HP@ Tolc but a lower reduction of metabolic activity and cell mass when compared with free tolcapone.…”

Synthetic Receptors for Early Detection and Treatment of Cancer

“…In recently published work, hydroxypropyl cyclodextrin has been shown again, probably by its cholesterol binding and depletion ability, to both impede breast cancer cell growth and cause cancer cell death [88]. Experiments using mouse xenografts have proved extremely promising, showing total eradication of early-stage tumours and what the authors describe as remarkable reductions in intermediate and late-stage tumours.…”