Quicknotes

From the Summer 2015 edition of Vanderbilt Medicine Magazine

Antibiotics with anticancer potential

The type II topoisomerases—enzymes that manage tangles and supercoils in DNA—exist in all organisms and are important drug targets. Widely prescribed anticancer agents including etoposide and doxorubicin target human type II topoisomerases, and quinolone antibiotics such as ciprofloxacin target bacterial topoisomerases.

Clinically relevant quinolones have no activity against human type II topoisomerases, but a series of experimental quinolones have high activity against both bacterial and human topoisomerases. To understand the basis for this quinolone cross-reactivity, Neil Osheroff, Ph.D., and colleagues analyzed the activity of one of the experimental compounds (CP-115,955) and a series of related quinolones and quinazolinediones against type II topoisomerases from Bacillus anthracis and humans.

They found that CP-115,955 uses different structural features, which they defined, to recognize both bacterial and human enzymes. The findings, reported in the Feb. 10 issue of Biochemistry, suggest that the CP-115,955 series quinolones may be a good starting point for developing novel topoisomerase II-targeted drugs with anticancer potential.


RNA defects in multiple sclerosis

Profound defects exist in the integrity of structural RNA molecules in patients with relapsing remitting multiple sclerosis (RRMS), a new study reports. RRMS is one type of multiple sclerosis, an inflammatory disease characterized by damage to the insulating myelin on nerve cells. The disease mechanisms that produce multiple sclerosis are not fully understood.

Thomas Aune, Ph.D., and colleagues used quantitative PCR and whole genome RNA sequencing to examine defects in structural RNA surveillance in blood immune cells from subjects with RRMS and in cell lines. Structural RNAs participate in a wide range of cellular processes, including protein production. The investigators found elevated levels of mis-processed structural RNAs, genome-wide defects in mRNA splicing and deficiencies in proteins that participate in quality control of structural RNAs. Betaseron, a common therapy for RRMS but not other autoimmune diseases, restored balance to structural RNAs.

The findings, reported March 25 in Genome Biology, establish that defects in structural RNAs exist in RRMS.


Boosting cell-based heart repair

Mesenchymal stem cells (MSCs)— adult stem cells traditionally found in bone marrow—have been used therapeutically to repair injured heart, soft tissue and bone. However, more than 100 clinical trials of MSCs in cardiovascular diseases have demonstrated only modest improvements in cardiac function.

To explore factors that may limit the potency of MSC-based regenerative therapy, Sarika Saraswati, Ph.D., Pampee Young, M.D., Ph.D., and colleagues evaluated the responses of MSCs to the low oxygen conditions (hypoxia) found in injured tissue. They reported in the April issue of Stem Cells that MSCs switch to anaerobic metabolism, and have dramatically increased expression of a monocarboxylate transporter (MCT4), a lactate exporter. Using a mouse model of cardiac injury, the investigators showed that MSCs expressing high levels of MCT4 worsened cardiac function, whereas MSCs with silenced MCT4 significantly improved cardiac function.

The findings reveal a metabolic alteration in MSCs that adversely affects cardiac repair, suggesting that strategies to prevent this response may boost MSC therapeutic efficacy.

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