Retraction Notice to: Nanoscale Metal-Organic Framework Mediates Radical Therapy to Enhance Cancer Immunotherapy.

[This retracts the article PMC6681452.].

Carnitine octanoyltransferase is important for the assimilation of exogenous acetyl-L-carnitine into acetyl-CoA in mammalian cells.

In eukaryotes, carnitine is best known for its ability to shuttle esterified fatty acids across mitochondrial membranes for ß-oxidation. It also returns to the cytoplasm, in the form of acetyl-L-carnitine (LAC), some of the resulting acetyl groups for posttranslational protein modification and lipid biosynthesis. While dietary LAC supplementation has been clinically investigated, its effects on cellular metabolism are not well understood. To explain how exogenous LAC influences mammalian cell metabolism, we synthesized isotope-labeled forms of LAC and its analogs. In cultures of glucose-limited U87MG glioma cells, exogenous LAC contributed more robustly to intracellular acetyl-CoA pools than did ß-hydroxybutyrate, the predominant circulating ketone body in mammals. The fact that most LAC-derived acetyl-CoA is cytosolic is evident from strong labeling of fatty acids in U87MG cells by exogenous 13C2-acetyl-L-carnitine. We found that the addition of d3-acetyl-L-carnitine increases the supply of acetyl-CoA for cytosolic posttranslational modifications due to its strong kinetic isotope effect on acetyl-CoA carboxylase, the first committed step in fatty acid biosynthesis. Surprisingly, whereas cytosolic carnitine acetyltransferase is believed to catalyze acetyl group transfer from LAC to coenzyme A, CRAT-/- U87MG cells were unimpaired in their ability to assimilate exogenous LAC into acetyl-CoA. We identified carnitine octanoyltransferase as the key enzyme in this process, implicating a role for peroxisomes in efficient LAC utilization. Our work has opened the door to further biochemical investigations of a new pathway for supplying acetyl-CoA to certain glucose-starved cells.

Palladium/norbornene-catalyzed distal alkenyl C-H arylation and alkylation of cis-olefins.

In this full article, a detailed study of a distal alkenyl C-H arylation and alkylation through the palladium/norbornene (NBE) cooperative catalysis is described. Both aminopyridine- and oxime ether-type directing groups have been found effective for this transformation, allowing functionalization of diverse allyl amines and homoallyl alcohols. In addition, the C5,C6-substititued NBEs show optimal reactivity and selectivity. Various cis-olefins can be transformed to the corresponding arylated or alkylated trisubstituted alkenes with excellent regio- and stereoselectivity. Preliminary mechanistic studies support the Catellani pathway instead of the Heck pathway.

Distal Alkenyl C-H Functionalization via the Palladium/Norbornene Cooperative Catalysis.

A distal-selective alkenyl C-H arylation method is reported through a directed palladium/norbornene (Pd/NBE) cooperative catalysis. The key is to use an appropriate combination of the directing group and the NBE cocatalyst. A range of acyclic and cyclic cis-olefins are suitable substrates, and the reaction is operated under air with excellent site-selectivity. Preliminary mechanistic studies are consistent with the proposed Pd/NBE-catalyzed C-H activation instead of the Heck pathway. Initial success on distal alkylation has also been achieved using MeI and methyl bromoacetate as electrophiles.

Nanoscale Metal-Organic Framework Mediates Radical Therapy to Enhance Cancer Immunotherapy.

Checkpoint blockade immunotherapy (CBI) elicits durable therapeutic responses by blocking T cell inhibitory pathways of tumors with pre-infiltrated T cells and/or high mutational burden to activate antitumor immunity but is ineffective against poorly immunogenic tumors. Immunogenic radiotherapy, photodynamic therapy (PDT), and chemotherapy have thus been examined as immunomodulatory adjuvants to augment CBI. Dysregulated hormone production has long been linked to tumorigenesis and poor prognosis of various cancers. Herein, we report the use of a Cu-porphyrin nanoscale metal-organic framework (nMOF) to mediate synergistic hormone-triggered chemodynamic therapy (CDT) and light-triggered PDT. The combination of CDT/PDT-based radical therapy with a programmed cell-death ligand 1 blockade effectively extends the local therapeutic effects of CDT/PDT to distant tumors via abscopal effects on mouse tumor models with high levels of estradiol. Our work thus establishes the feasibility of combining nMOF-mediated radical therapy with CBI to elicit systemic antitumor immunity in hormonally dysregulated tumor phenotypes.