Abstract
Overexpression of glucose transporters (GLUTs) in colorectal cancer cells is associated with 5-fluorouracil (1, 5-FU) resistance and poor clinical outcomes. We designed and synthesized a novel GLUT-targeting drug conjugate, triggered by glutathione in the tumor microenvironment, that releases 5-FU and GLUTs inhibitor (phlorizin (2) and phloretin (3)). Using an orthotopic colorectal cancer mice model, we showed that the conjugate exhibited better antitumor efficacy than 5-FU, with much lower exposure of 5-FU during treatment and without significant side effects. Our study establishes a GLUT-targeting theranostic incorporating a disulfide linker between the targeting module and cytotoxic payload as a potential antitumor therapy.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Antineoplastic Agents / chemistry*
-
Antineoplastic Agents / metabolism
-
Antineoplastic Agents / pharmacology
-
Antineoplastic Agents / therapeutic use
-
Cell Line, Tumor
-
Cell Survival / drug effects
-
Colorectal Neoplasms / chemically induced
-
Colorectal Neoplasms / drug therapy
-
Colorectal Neoplasms / metabolism
-
Disease Models, Animal
-
Drug Stability
-
Enzyme Inhibitors / chemistry*
-
Enzyme Inhibitors / metabolism
-
Enzyme Inhibitors / pharmacology
-
Enzyme Inhibitors / therapeutic use
-
Fluorouracil / therapeutic use
-
Glucose Transport Proteins, Facilitative / antagonists & inhibitors*
-
Glucose Transport Proteins, Facilitative / metabolism
-
Half-Life
-
Humans
-
Mice
-
Mice, Inbred BALB C
-
Phloretin / chemistry
-
Phloretin / metabolism
-
Phloretin / therapeutic use
-
Phlorhizin / chemistry
-
Phlorhizin / metabolism
-
Phlorhizin / therapeutic use
-
Structure-Activity Relationship
-
Tissue Distribution
Substances
-
Antineoplastic Agents
-
Enzyme Inhibitors
-
Glucose Transport Proteins, Facilitative
-
Phlorhizin
-
Phloretin
-
Fluorouracil