Date Published: June 7, 2019
Publisher: Public Library of Science
Author(s): Amila K. Nanayakkara, Pia D. Vogel, John G. Wise, Jed N. Lampe.
One common reason for cancer chemotherapy failure is increased drug efflux catalyzed by membrane transporters with broad pump substrate specificities, which leads to resistances to a wide range of chemically unrelated drugs. This multidrug resistance (MDR) phenomenon results in failed therapies and poor patient prognoses. A common cause of MDR is over-expression of the P-glycoprotein (ABCB1/P-gp) transporter. We report here on an MDR modulator that is a small molecule inhibitor of P-glycoprotein, but is not a pump substrate for P-gp and we show for the first time that extended exposure of an MDR prostate cancer cell line to the inhibitor following treatment with chemotherapeutics and inhibitor resulted in trapping of the chemotherapeutics within the cancerous cells. This trapping led to decreased cell viability, survival, and motility, and increased indicators of apoptosis in the cancerous cells. In contrast, extended exposure of non-Pgp-overexpressing cells to the inhibitor during and after similar chemotherapy treatments did not lead to decreased cell viability and survival, indicating that toxicity of the chemotherapeutic was not increased by the inhibitor. Increases in efficacy in treating MDR cancer cells without increasing toxicity to normal cells by such extended inhibitor treatment might translate to increased clinical efficacy of chemotherapies if suitable inhibitors can be developed.
Chemotherapy treatments are often part of cancer therapies, either before surgery to decrease the size of existing tumors, or after surgery to target metastatic cells that may have migrated out of the primary site of the disease. For cancers that are not surgically accessible, chemotherapy is often the only treatment option. Some of these therapies can be remarkably effective, but unfortunately many cancers recur after initial, seemingly successful treatments and still others simply do not respond well to chemotherapies . One common reason for the failure of chemotherapies is the expression of biochemical defense mechanisms in the cancer cells that have evolved to keep normal cells and tissues healthy. The phenomenon of multidrug resistances (MDR) in cancer chemotherapies is one such example, where certain members of the ABC transporter superfamily of membrane proteins , when expressed in cancerous cells, actively keep the cells free of the cytotoxic chemotherapeutics [3–8]. When expressed at high levels, proteins like P-glycoprotein (ABCB1, P-gp) , the breast cancer resistance protein (ABCG2, BCRP) , and/or the multidrug resistance associated protein 1 (ABCC1, MRP-1) , have the ability to remove most of the approved cancer chemotherapeutics from the cells, making chemotherapies ineffective.
The balance between chemotherapy effectiveness and its associated toxicities to normal cells and tissues has been the principle limit to the clinical efficacy of cancer chemotherapies. Contributing to this problem have been intrinsic or acquired resistances to chemotherapeutics that limit effectiveness on the targeted cancer cells. These resistances usually do not extend to normal cells and therefore do not protect the normal cells from the toxicities of the therapeutic agents (see for example ). The phenomenon of multidrug resistance caused by the over-expression of ABC transporter drug efflux pumps that have broad pump substrate specificities like P-glycoprotein has been particularly problematic due to the fact that these cellular defense proteins can limit the intracellular concentrations of drugs to sub-therapeutic levels specifically in the cancer cells [35, 36]. Especially troubling as a potential cause of cancer recurrence after apparently successful treatment is the cancer stem cell hypothesis [37–40] that posits that a subpopulation of cancer cells, well-protected by ABC transporter efflux pumps, may be responsible for the long-term growth and resistance of many cancers to chemo- and radiation therapies. The significant unmet medical need for targeted therapies against these MDR cancer cell defenses is therefore obvious.