Tag Archives: mitochondria

MIT Develops New Platinum Compound As Powerful As Cisplatin But Better Able To Destroy Tumor Cells

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MIT chemists have developed a new platinum compound that is as powerful as the commonly used anticancer drug cisplatin but better able to destroy tumor cells.

A diagram of cisplatin which is a platinum chemotherapy drug.

Massachusetts Institute of Technology chemists have developed a new platinum compound that is as powerful as the commonly

Stephen J. Lippard Ph.D., Arthur Amos Noyes Professor of Chemistry, Massachusetts Institute of Technology

used anticancer drug cisplatin but better able to destroy tumor cells.

The new compound, mitaplatin, combines cisplatin with another compound, dichloroacetate (DCA), which can alter the properties of mitochondria selectively in cancer cells. Cancer cells switch their mitochondrial properties to change the way they metabolize glucose compared to normal cells, and DCA specifically targets the altered mitochondria, leaving normal cells intact.

“This differential effect conveys on mitaplatin the ability to kill cancer cells selectively in a co-culture with normal fibroblast cells, the latter being unaffected at the doses that we apply,” says Stephen Lippard, the Arthur Amos Noyes Professor of Chemistry.

How they did it: The chemists designed mitaplatin so that when it enters a cell, it releases cisplatin and two units of DCA by intracellular reduction. Therefore, mitaplatin can attack nuclear DNA with cisplatin and mitochondria with DCA. DCA promotes the release of cell-death-promoting factors from the mitochondria, enhancing the cancer cell-killing abilities of cisplatin.

Next steps: Lippard’s laboratory has shown that in rodents, mitaplatin can be tolerated at much higher doses than cisplatin, and they have begun studies in mice transplanted with human tissues. If those results are promising, the researchers plan more studies for further demonstration of mitaplatin’s ability in cancer therapy.

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What’s Feeding Cancer Cells? — Johns Hopkins Researchers Discover How Critical Cancer Gene Controls Nutrient Use.

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“Cancer cells need a lot of nutrients to multiply and survive. While much is understood about how cancer cells use blood sugar to make energy, not much is known about how they get other nutrients. Now, researchers at the Johns Hopkins University School of Medicine have discovered how the Myc cancer-promoting gene uses microRNAs to control the use of glutamine, a major energy source. The results, which shed light on a new angle of cancer that might help scientists figure out a way to stop the disease, appear Feb. 15 online at Nature. …”

“February 15, 2009- Cancer cells need a lot of nutrients to multiply and survive. While much is understood about how cancer cells use blood sugar to make energy, not much is known about how they get other nutrients. Now, researchers at the Johns Hopkins University School of Medicine have discovered how the Myc cancer-promoting gene uses microRNAs to control the use of glutamine, a major energy source. The results, which shed light on a new angle of cancer that might help scientists figure out a way to stop the disease, appear Feb. 15 online at Nature.

Chi Dang, M.D., Ph.D. The Johns Hopkins Family Professor in Oncology Research; Professor of Medicine, Cell Biology, Oncology and Pathology; and Vice Dean for Research, School of Medicine

Chi Dang, M.D., Ph.D. The Johns Hopkins Family Professor in Oncology Research; Professor of Medicine, Cell Biology, Oncology and Pathology; and Vice Dean for Research, School of Medicine

‘While we were looking for how Myc promotes cancer growth, it was unexpected to find that Myc can increase use of glutamine by cancer cells,’ says Chi V. Dang, M.D., Ph.D., the Johns Hopkins Family Professor of Oncology at Johns Hopkins. ‘This surprising discovery only came about after scientists from several disciplines came together across Hopkins to collaborate — it was a real team effort.’

In their search to learn how Myc promotes cancer, the researchers teamed up with protein experts, and using human cancer cells with Myc turned on or off, they looked for proteins in the cell’s powerhouse — the mitochondria — that appeared to respond to Myc. They found eight proteins that were distinctly turned up in response to Myc.

At the top of the list of mitochondrial proteins that respond to Myc was glutaminase, or GLS, which, according to Dang, is the first enzyme that processes glutamine and feeds chemical reactions that make cellular energy. So the team then asked if removing GLS could stop or slow cancer cell growth. Compared to cancer cells with GLS, those lacking GLS grew much slower, which led the team to conclude that yes, GLS does affect cell growth stimulated by Myc.

The researchers then wanted to figure out how Myc enhances GLS protein expression. Because Myc can control and turn on genes, the team guessed that Myc might directly turn on the GLS gene, but they found that wasn’t the case. ‘So then we thought, maybe there’s an intermediary, maybe Myc controls something that in turn controls GLS,’ says Ping Gao, Ph.D., a research associate in hematology at Johns Hopkins.

They then built on previous work done with the McKusick-Nathans Institute of Genetic Medicine at Hopkins where they discovered that Myc turns down some microRNAs, small bits of RNA that can bind to and inhibit RNAs, which contain instructions for making proteins. The team looked more carefully at the GLS RNA and found that it could be bound and regulated by two microRNAs, called miR23a and miR23b, pointing to the microRNAs as the intermediary that links Myc to GLS expression.

‘Next we want to study GLS in mice to see if removing it can slow or stop cancer growth,’ says Gao. ‘If we know how cancer cells differ from normal cells in how they make energy and use nutrients, we can identify new pathways to target for designing drugs with fewer side effects.’

This study was funded by the National Institutes of Health, the National Cancer Institute, the Rita Allen Foundation, the Leukemia and Lymphoma Society and the Sol Goldman Center for Pancreatic Cancer Research.

Authors on the paper are Ping Gao, Irina Tchernyshyov, Tsung-Cheng Chang, Yun-Sil Lee, Karen Zeller, Angelo De Marzo, Jennifer Van Eyk, Joshua Mendell and Chi V. Dang, of Johns Hopkins; and Kayoko Kita and Takfumi Ochi of Teikyo University in Japan.

On the Web:
http://www.hopkinsmedicine.org/hematology/faculty_staff/dang.html
http://www.proteomics.jhu.edu/index.php
http://www.hopkinsmedicine.org/geneticmedicine/People/Faculty/mendell.html
http://www.nature.com/nature/index.html

– JHM –

Media Contacts: Audrey Huang; 410-614-5105; audrey@jhmi.edu
Maryalice Yakutchik; 443-287-2251; myakutc1@jhmi.edu”

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Quoted Source:  What’s Feeding Cancer Cells? – Johns Hopkins Researchers Discover How Critical Cancer Gene Controls Nutrient Use, Press Release, Johns Hopkins Medicine, February 15, 2009.

Primary Citation:  c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism; Ping Gao, Irina Tchernyshyov, Tsung-Cheng Chang et. al., Letter, Nature advance online publication 15 February 2009.