2 research outputs found
Chloroquine-Modified Hydroxyethyl Starch as a Polymeric Drug for Cancer Therapy
Hydroxyethyl
starch (HES) is a clinically used polysaccharide colloidal
plasma volume expander. The goal of this study was to synthesize HES
modified with hydroxychloroquine (HCQ) as a novel polymeric drug with
the ability to inhibit the invasive character of pancreatic cancer
(PC) cells. HES was conjugated with HCQ using a simple carbonyldiimidazole
coupling to prepare Chloroquine-modified HES (CQ-HES). CQ-HES with
various degrees of HCQ substitution were synthesized and characterized.
Atomic force microscopy was used to demonstrate a pH-dependent assembly
of CQ-HES into well-defined nanoparticles. <i>In vitro</i> studies in multiple PC cell lines showed CQ-HES to have a similar
toxicity profile as HCQ. Confocal microscopy revealed the propensity
of CQ-HES to localize to lysosomes and mechanistic studies confirmed
the ability of CQ-HES to inhibit autophagy in PC cells. Further studies
demonstrated a greatly enhanced ability of CQ-HES to inhibit the migration
and invasion of PC cells when compared with HCQ. The enhanced inhibitory
actions of CQ-HES compared to HCQ appeared to arise in part from the
increased inhibition of ERK and Akt phosphorylation. We found no significant
HCQ release from CQ-HES, which confirmed that the observed activity
was due to the action of CQ-HES as a polymeric drug. Due to its promising
ability to block cancer cell invasion and the ability to form nanoparticles,
CQ-HES has the potential as a drug delivery platform suitable for
future development with chemotherapeutics to establish novel antimetastatic
treatments
Additional file 1: of WDR5 supports colon cancer cells by promoting methylation of H3K4 and suppressing DNA damage
Table S1. Frequency of KMT2/MLL Mutations in Colon Cancer Cell Lines. Table S2. Sequences of individual siRNA and shRNA duplexes. Table S3. Sequences of qPCR primers. Figure S1. Validation of four oligos used for RNAi-mediated WDR5 depletion. Figure S2. Drug dose response curve for OICR-9429 in HCT116 cells. Figure S3. Representative propidium iodide cell cycle analysis following WDR5 depletion or OICR-9429 treatment in three colon cancer cell lines. Figure S4. Evaluation of apoptosis via Annexin V/PI staining following WDR5 depletion or OICR-9429 treatment in three colon cancer cell lines. Figure S5. RBBP5 depletion does not affect cell viability in a panel of colon cancer cell lines. (PDF 394Â kb