Nanodiamond autophagy inhibitor allosterically improves the arsenical-based therapy of solid tumors

Abstract

Arsenic trioxide (ATO) is a successful chemotherapeutic drug for blood cancers via selective induction of apoptosis; however its efficacy in solid tumors is limited. Here we repurpose nanodiamonds (NDs) as a safe and potent autophagic inhibitor to allosterically improve the therapeutic efficacy of ATO-based treatment in solid tumors. We find that NDs and ATO are physically separate and functionally target different cellular pathways (autophagy vs. apoptosis); whereas their metabolic coupling in human liver carcinoma cells remarkably enhances programmed cell death. Combination therapy in liver tumor mice model results in ~91% carcinoma decrease as compared with ~28% without NDs. Treated mice show 100% survival rate in 150 days with greatly reduced advanced liver carcinoma-associated symptoms, and ~80% of post-therapy mice survive for over 20 weeks. Our work presents a novel strategy to harness the power of nanoparticles to broaden the scope of ATO-based therapy and more generally to fight solid tumors.

Development of a pH-responsive polymersome inducing endoplasmic reticulum stress and autophagy blockade

“…The expression of p62 (sequestosome-1) as an autophagy substrate can characterize the smoothness of the autophagic flux. When the autophagic level is increased and the autophagic flux is smooth, the expression of LC3-II is increased and the expression of p62 is decreased; however, when the autophagy level is increased and the autophagic flux is blocked, the expression of both LC3-II and p62 is increased (39,40). As shown in Fig.…”

Pyridinium‐Substituted Tetraphenylethylenes Functionalized with Alkyl Chains as Autophagy Modulators for Cancer Therapy

“…Compared with untreated cells, a stronger intensity of fluorescent puncta was observed, confirming the induction of autophagy by complexes 1 – 3 . Furthermore, cell transfection experiments were also performed using GFP‐LC3B plasmid to verify the proautophagy activity of complexes 1 – 3 (Supporting Information, page S18) …”

Augmenting Tumor‐Starvation Therapy by Cancer Cell Autophagy Inhibition

“…In general, nanomedicine internalization will provoke mild cytoprotective autophagic responses as these extraneous particles may influence intracellular homeostasis . Notably, several nanomaterials, such as nanodiamonds and titania‐coated gold nanoparticles, have been demonstrated to be capable of inhibiting autophagy via multiple pathways. A recent report indicates that black phosphorus (BP) nanosheets, which have been explored as robust biodegradable therapeutic platforms in various biomedical settings, could block autophagy flux and aggravate aberrant autophagosomes accumulation .…”