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Scientists Unveil Why Non-Specific Occurrence of Multidrug-Resistance Arises During Tumour Therapy

Non-substrate chemicals have been shown to induce multidrug resistance by causing oxidative stress when tested on specific transporters.

Accounting for nearly one in six deaths, cancer is one of the leading causes of death worldwide. To treat cancer, chemotherapy is often applied to kill cancer cells. Unfortunately, cancers can develop resistance to therapies, thereby increasing the prevalence of drug-resistant cancers, which eventually develop into multidrug resistance thereby rendering most drugs ineffective. Now, researchers from the Suzhou Institute of Biomedical Engineering and Technology (SIBEBT) of the Chinese Academy of Sciences (CAS) have discovered several possible reasons why multi-drug resistance inevitably occurs during tumour therapy.

Of the many mechanisms of drug resistance, one of the most well-studied mechanisms is the induction of Adenosinetriphosphate (ATP)-binding cassette (ABC) transporters by chemotherapeutic drugs. Highly expressed in cancer cells, these transporters can pump out chemotherapeutics and make the treatment ineffective. According to a previous study, non-substrate nanoparticles could induce multidrug resistance by causing oxidative damage, indicating that multidrug resistance could be induced by not only the substrates but also oxidative damage.

To verify this claim, Yin Jian and his team at SIBEBT used a lung cancer cell line as a model to study the interaction of doxorubicin, ethanol, and hydrogen peroxide with ABC transporters. Doxorubicin is the substrate of ABC transporter and chemotherapeutic drugs, whereas ethanol and hydrogen peroxide are small-molecule compounds that are unrelated to the function of ABC transporter.

“When the three substances enter the cells, they can cause significant oxidative stress inside cells,” said Yin Jian.

With increased oxidative stress, the expression of transporters is elevated, which in turn decreases intracellular oxidative stress by effluxing oxidised glutathione. In this process, pregnane X receptor played an important regulatory role. These results indicate that non-substrate chemicals could also induce ABC transporter expressions like that of chemotherapeutic agents upon inducing oxidative damage. This phenomenon could be regarded as a non-specific feedback of tumour cells/ABC transporters to external stimuli.

With these results, the researchers successfully established the relationship between multidrug resistance mechanisms and oxidative stress. Their findings are expected to help innovate advanced strategies to enhance this mechanism to better combat ABC transporter-mediated multidrug resistance.

“Considering that peroxidative damage is the main source of the toxicity of current environmental pollutants, long-term exposure to environmental pollutants could not only induce direct toxicity, but also further threaten human health by inducing multi-drug resistance,” said Yin Huancai, another researcher from the study. [APBN]

Source: Yuan et al. (2022). Oxidative stress-mediated up-regulation of ABC transporters in lung cancer cells. Journal of Biochemical and Molecular Toxicology, e23095.