Mithramycin inhibits etoposide resistance in glucose-deprived HT-29 human colon carcinoma cells

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Physiological conditions like glucose deprivation and hypoxia contribute to drug resistance in solid tumors.
• These conditions decrease DNA topoisomerase IIalpha expression, leading to resistance against drugs like etoposide.
• Targeting tumor-specific environments, such as low glucose, presents a novel strategy for anticancer drug development.

Purpose of the Study:

• To establish a screening program for anticancer agents with preferential cytotoxic activity under glucose-deprived conditions.
• To identify and characterize novel compounds that can overcome drug resistance induced by tumor microenvironments.
• To investigate the potential of mithramycin in preventing etoposide resistance under specific metabolic conditions.

Main Methods:

• Screening of anticancer agents for activity in glucose-deprived cancer cells.
• Isolation and identification of active compounds using LC-MS and NMR spectroscopy.
• In vitro assessment of compound efficacy in preventing etoposide resistance in HT-29 colon cancer cells under varying glucose concentrations.

Main Results:

• An active compound, AA-98, was isolated from Streptomyces sp. AA030098.
• AA-98 was identified as mithramycin, an aureolic acid group antitumor compound.
• Mithramycin effectively prevented etoposide resistance induced by glucose deprivation and selectively killed resistant HT-29 cells in a low-glucose environment.

Conclusions:

• Mithramycin demonstrates selective cytotoxicity against etoposide-resistant cancer cells under specific low-glucose conditions.
• The chemosensitive action of mithramycin is dependent on strict glucose deprivation, highlighting its potential in targeting tumor-specific metabolic vulnerabilities.
• Targeting metabolic stress in tumors represents a promising approach for developing novel anticancer therapies that overcome drug resistance.