Researchers at Southern Methodist University have discovered three drug-like compounds that successfully reverse chemotherapy failure in three of the most commonly aggressive cancers - ovarian, prostate and breast. The molecules were first discovered computationally via high-performance supercomputing. Now their effectiveness against specific cancers has been confirmed via wet-lab experiments, said biochemistry professors Pia Vogel and John G. Wise, who led the study.
Wise and Vogel report the advancement in the Nature journal Scientific Reports.
The computational discovery was confirmed in the Wise-Vogel labs at SMU after aggressive micro-tumors cultured in the labs were treated with a solution carrying the molecules in combination with a classic chemotherapy drug. The chemotherapy drug by itself was not effective in treating the drug-resistant cancer.
"Nature designs all cells with survival mechanisms, and cancer cells are no exception," said Vogel, a professor and director of SMU's Center for Drug Discovery, Design and Delivery. "So it was incredibly gratifying that we were able to identify molecules that can inhibit that mechanism in the cancer cells, thereby bolstering the effectiveness of chemotherapeutic drugs. We saw the drugs penetrate these resistant cancer cells and allow chemotherapy to destroy them. While this is far from being a developed drug that will be available on the market anytime soon, this success in the lab gives us hope for developing new drugs to fight cancer."
The current battle to defeat cancer is thwarted by chemotherapy failure in advanced cancers. Cancer cells initially treated with chemotherapy drugs ultimately evolve to resist the drugs. That renders chemotherapy ineffective, allowing cancers to grow and spread.
Key to cancer cell resistance are often certain proteins typically found in all cells - cancerous or otherwise - that are outfitted with beneficial mechanisms that pump away toxins to ensure a cell's continued survival. Nature has set it up that these pumps are prevalent throughout the body, with some areas naturally having more of the pumps than others.
"The cancer cell itself can use all these built-in defenses to protect it from the kinds of things we're using to try to kill it with," Wise said.
The most common of these beneficial defense mechanisms is a pump protein, P-glycoprotein or P-gp, as it's called. Another is one seen in breast and many other cancers, called breast cancer resistance protein, BCRP. In the case of cancer cells on the first round of treatment, these pumps are typically not produced in high levels in the cells, which allows chemotherapy to enter most of the cells in the tumor. This often gives what looks like a good result.
Unfortunately, in the cancer cells that don't die, the chemotherapeutic often changes the cell, which then adapts to protect itself by aggressively multiplying the production of its defensive pumps.
Upon subsequent rounds of chemo, the P-gp and BCRP pumping mechanisms have proliferated. They effectively resist the chemotherapy, which now is much less successful, or not successful at all.
"if enough of the pumps are present, the cancer isn't treatable anymore," said Wise, associate professor in the SMU Department of Biological Sciences. Researchers in the field have searched unsuccessfully for compounds to inhibit the pumps that could be used in the clinic as well.
The molecules that Wise and Vogel discovered stopped the pumps.
"They effectively bring the cancer cells back to a sensitivity as if they'd never seen chemotherapy before," said Vogel. "And our data indicated the molecules aren't cancer specific. They can be used to treat all kinds of cancers because they inhibit not just the P-gp pump, but also the breast cancer protein pump."
To test the compounds, the researchers used amounts of chemotherapeutic that would not kill these multi-drug resistant cancer...
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