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Cocktail proves toxic to leukemia cells

Rice University, MD Anderson research points toward better personalized therapy

A combination of drugs that affect mitochondria — the power plants inside cells — may become the best weapons yet to fight acute myeloid leukemia, according to Rice University researchers.

A study led by Rice bioscientist Natasha Kirienko and postdoctoral researcher Svetlana Panina found that mitocans, anti-cancer drugs that target mitochondria, are particularly adept at killing leukemia cells, especially when combined with a glycolytic inhibitor, while leaving healthy blood cells in the same sample largely unaffected.

Their open access paper, a collaboration with the University of Texas MD Anderson Cancer Center, appears in the Nature journal Cell Death & Disease. The research could lead to new ways to personalize treatment for patients with leukemia.
“We started with the idea of finding an underlying connection between types of cancer and their sensitivity to specific kinds of chemotherapeutics, mitochondria-targeting drugs,” Kirienko said. “Our bioinformatic analysis, which included 60 cell lines from nine different cancer types, showed that leukemia cells are particularly sensitive to mitochondrial damage.”

The researchers exposed the cell lines to multiple known mitocan molecules. They found low doses of a mitocan/glycolytic inhibitor cocktail killed all of the leukemia cell lines they tested at concentrations lower than what was necessary to kill healthy cells. Conversely, they reported that solid tumor cells, like ovarian cancers, proved highly resistant to mitocans. Glioblastoma cells were sensitive to mitocans, but unfortunately more resistant than healthy blood cells.

In their best experimental results, 86% of targeted leukemia cells were killed, compared to only 30% of healthy blood cells. “A number of drugs currently used in the clinic have some cancer preference, but here we’re talking about a five-fold difference in survival,” Kirienko said.
The researchers also showed a significant correlation between how efficiently mitochondria can turn energy from incoming oxygen into useful adenosine triphosphate (ATP) and how resistant they are to treatment.

“The more efficient they are, the more resistant they will be to mitochondria-targeting drugs,” Kirienko said. “If this holds true, doctors can perform a relatively simple test of this specific parameter of mitochondrial health from a patient’s sample and predict whether the treatment would be effective.”
Panina said computational models led them to think the glycolysis pathway could be enlisted to help mitocans. “Glycolysis also provides ATP, so targeting that will decrease energy as well as block the precursor for energy production in mitochondria, which mitocans will exacerbate further,” she said. “It led us to believe this combination would have a synergistic effect.

“Cancer cells are usually more metabolically active than normal cells, so we predicted that they be might be more sensitive to this combined strike, and they are,” Panina said.

Kirienko said a presentation of the research she and Panina gave at MD Anderson’s recent Metabolism in Cancer Symposium drew a large response. “People were very interested, and they immediately started asking, ‘Did you test my favorite drug or combination?’ and ‘Are you going to test it in a wider panel of cancers?’”

That work is well underway, Panina said. “We’re currently doing high-throughput screening of these potential synergistic drug combinations against leukemia cells,” she said. “We’ve gone through 36 combinations so far, building landscapes for each one.”
“And we found some that are more effective than what’s reported in this paper,” Kirienko added. “But we’ve also found some that are antagonistic — two drugs that negate each other’s effects — so it’s also important to know what therapeutic cocktails should not go together.”

Co-authors of the paper are postdoctoral fellow Natalia Baran; Marina Konopleva, a physician-scientist and professor in the Department of Leukemia at MD Anderson; and Rice graduate student Fabio Brasil da Costa. Kirienko is an assistant professor of biosciences.
The Cancer Prevention Research Institute of Texas, the Welch Foundation and the National Institutes of Health supported the research.

Read the paper at https://www.nature.com/articles/s41419-019-1851-3.pdf.

This news release can be found online at https://news.rice.edu/2019/10/31/cocktail-proves-toxic-to-leukemia-cells/

Follow Rice News and Media Relations via Twitter @RiceUNews.

Related materials:


Kirienko Lab: http://kirienkolab.rice.edu/index.html
Marina Konopleva: https://faculty.mdanderson.org/profiles/marina_konopleva.html
Rice Department of BioSciences: https://biosciences.rice.edu
Wiess School of Natural Sciences: https://naturalsciences.rice.edu

Damaged Hearts rewired

Thin, flexible fibers made of carbon nanotubes  have now proven able to bridge damaged heart tissues and deliver the electrical signals needed to keep those hearts beating.

At Texas Heart Institute (THI) report they have used biocompatible fibers invented at Rice University in studies that showed sewing them directly into damaged tissue can restore electrical function to hearts.

“Instead of shocking and defibrillating, we are actually correcting diseased conduction of the largest major pumping chamber of the heart by creating a bridge to bypass and conduct over a scarred area of a damaged heart,” said Dr. Mehdi Razavi, a cardiologist and director of Electrophysiology Clinical Research and Innovations at THI, who co-led the study with Rice chemical and biomolecular engineer Matteo Pasquali.

“Today there is no technology that treats the underlying cause of the No. 1 cause of sudden death, ventricular arrhythmias,” Razavi said. “These arrhythmias are caused by the disorganized firing of impulses from the heart’s lower chambers and are challenging to treat in patients after a heart attack or with scarred heart tissue due to such other conditions as congestive heart failure or dilated cardiomyopathy.”

Results of the studies on preclinical models appear as an open-access Editor’s Pick in the American Heart Association’s Circulation: Arrhythmia and Electrophysiology. The association helped fund the research with a 2015 grant. The research springs from the pioneering 2013 invention by Pasquali’s lab of a method to make conductive fibers out of carbon nanotubes. The lab’s first threadlike fibers were a quarter of the width of a human hair, but contained tens of millions of microscopic nanotubes. The fibers are also being studied for electrical interfaces with the brain, for use in cochlear implants, as flexible antennas and for automotive and aerospace applications.

The experiments showed the nontoxic, polymer-coated fibers, with their ends stripped to serve as electrodes, were effective in restoring function during monthlong tests in large preclinical models as well as rodents, whether the initial conduction was slowed, severed or blocked, according to the researchers. The fibers served their purpose with or without the presence of a pacemaker, they found.

In the rodents, they wrote, conduction disappeared when the fibers were removed. “The reestablishment of cardiac conduction with carbon nanotube fibers has the potential to revolutionize therapy for cardiac electrical disturbances, one of the most common causes of death in the United States,” said co-lead author Mark McCauley, who carried out many of the experiments as a postdoctoral fellow at THI. He is now an assistant professor of clinical medicine at the University of Illinois College of Medicine.

“Our experiments provided the first scientific support for using a synthetic material-based treatment rather than a drug to treat the leading cause of sudden death in the U.S. and many developing countries around the world,” Razavi added. Many questions remain before the procedure can move toward human testing, Pasquali said. The researchers must establish a way to sew the fibers in place using a minimally invasive catheter, and make sure the fibers are strong and flexible enough to serve a constantly beating heart over the long term. He said they must also determine how long and wide fibers should be, precisely how much electricity they need to carry and how they would perform in the growing hearts of young patients.

“Flexibility is important because the heart is continuously pulsating and moving, so anything that’s attached to the heart’s surface is going to be deformed and flexed,” said Pasquali, who has appointments at Rice’s Brown School of Engineering and Wiess School of Natural Sciences.

“Good interfacial contact is also critical to pick up and deliver the electrical signal,” he said. “In the past, multiple materials had to be combined to attain both electrical conductivity and effective contacts. These fibers have both properties built in by design, which greatly simplifies device construction and lowers risks of long-term failure due to delamination of multiple layers or coatings.” Razavi noted that while there are many effective antiarrhythmic drugs available, they are often contraindicated in patients after a heart attack. “What is really needed therapeutically is to increase conduction,” he said. “Carbon nanotube fibers have the conductive properties of metal but are flexible enough to allow us to navigate and deliver energy to a very specific area of a delicate, damaged heart.” Rice alumna Flavia Vitale, now an assistant professor of neurology and of physical medicine and rehabilitation at the University of Pennsylvania, and Stephen Yan, a graduate student at Rice, are co-lead authors of the paper.

Co-authors are Colin Young and Julia Coco of Rice; Brian Greet of THI and Baylor St. Luke’s Medical Center; Marco Orecchioni and Lucia Delogu of the Città della Speranza Pediatric Research Institute, Padua, Italy; Abdelmotagaly Elgalad, Mathews John, Doris Taylor and Luiz Sampaio, all of THI; and Srikanth Perike of the University of Illinois at Chicago. Pasquali is the A.J. Hartsook Professor of Chemical and Biomolecular Engineering, a professor of materials science and nanoengineering and of chemistry.

The American Heart Association, the Welch Foundation, the Air Force. Office of Scientific Research, the National Institutes of Health and Louis Magne supported the research.

Credit James Philpot/Texas Heart Institute