The study, “Targeted inhibitors of P-glycoprotein increase chemotherapeutic-induced mortality of multidrug resistant tumor cells” was published in the open access journal Scientific Reports.
One of the strategies cancer cells use to resist therapies is to increase the number of pumps (transporters) that sit at the membrane and pump out the toxic compounds that compose anti-cancer therapies. While these pumps occur naturally in our cells, cancer cells can increase their numbers for their own benefit. As a consequence, chemotherapy efficacy is largely reduced and the tumor is allowed to grow and spread.
“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,” study co-lead author John G. Wise at The Center for Drug Discovery, Design and Delivery, the Center for Scientific Computing, Southern Methodist University, in Dallas, Texas, said in a press release.
In cancer cells, including those in prostate tumors, the most common pump is P-glycoprotein or P-gp, but scientists have been unsuccessful in designing therapies to inhibit these pumps.
“There are currently no approved drugs available for clinical use in cancer chemotherapies to reverse MDR [multidrug resistance] by inhibiting P-glycoprotein,” the researchers wrote.
But using computational methods, the team identified several compounds that would likely inhibit P-gp. They then confirmed their activity by combining the compounds with chemotherapy in treatment-resistant cells. The compounds significantly decreased prostate cancer cells’ viability and survival compared with chemotherapy alone.
“They effectively bring the cancer cells back to a sensitivity as if they’d never seen chemotherapy before,” said biochemistry professor and study co-lead author Pia 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.”
Similar results were obtained for ovarian cancer cells and, to a lesser degree, for breast cancer cells expressing a pump called breast cancer resistance protein, or BCRP.
“The inhibitors increased cellular retention of chemotherapeutics and reporter compounds known to be transport substrates of P-gp,” the researchers wrote.
“Nature designs all cells with survival mechanisms, and cancer cells are no exception,” said Vogel, who is 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,” she added. “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.”
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