Abstract
One of the crucial challenges in the clinical management of cancer is resistance to chemotherapeutics. Multidrug resistance (MDR) has been intensively studied, and one of the most prominent mechanisms underlying MDR is overexpression of adenosine triphosphate (ATP)-binding cassette (ABC) transporters. Despite research efforts to develop compounds that inhibit the efflux activity of ABC transporters and thereby increase classical chemotherapy efficacy, to date, the Food and Drug Administration (FDA) has not approved the use of any ABC transporter inhibitors due to toxicity issues. Hedgehog signaling is aberrantly activated in many cancers, and has been shown to be involved in chemotherapy resistance. Recent studies showed that the Hedgehog receptor Ptch1, which is over-expressed in many recurrent and metastatic cancers, is a multidrug transporter and it contributes to the efflux of chemotherapeutic agents such as doxorubicin, and to chemotherapy resistance. Remarkably, Ptch1 uses the proton motive force to efflux drugs, in contrast to ABC transporters, which use ATP hydrolysis. Indeed, the “reversed pH gradient” that characterizes cancer cells, allows Ptch1 to function as an efflux pump specifically in cancer cells. This makes Ptch1 a particularly attractive therapeutic target for cancers expressing Ptch1, such as lung, breast, prostate, ovary, colon, brain, adrenocortical carcinoma, and melanoma. Screening of chemical libraries have identified several molecules that are able to enhance the cytotoxic effect of different chemotherapeutic agents by inhibiting Ptch1 drug efflux activity in different cancer cell lines that endogenously over-express Ptch1. In vivo proof of concept has been performed in mice where combining one of these compounds with doxorubicin prevented the development of xenografted adrenocortical carcinoma tumors more efficiently than doxorubicin alone, and without obvious undesirable side effects. Therefore, the use of a Ptch1 drug efflux inhibitor in combination with classical or targeted therapy could be a promising therapeutic option for Ptch1-expressing cancers.
Highlights
Despite the major progress that has been made in biomedical research, and the development of novel therapeutic strategies, cancer is still among the dominant causes of death worldwide [1].One of the crucial challenges in the clinical management of cancer is primary and secondary resistance to both conventional and targeted chemotherapeutics.Cancer is a complex disease and it represents the result of the progressive accumulation of genetic aberrations and epigenetic changes that escaped from the regular cellular and environmental controls.Cancer cells usually acquire genetic aberration including aneuploidy, chromosomal rearrangement, loss or gain of function mutations, deletions, gene rearrangements and amplifications [2].Cells 2018, 7, 107; doi:10.3390/cells7080107 www.mdpi.com/journal/cellsChemotherapy is one of the major treatments for cancer
Binding of Hh ligand to Ptch1 leads to its internalization and degradation. This process relieves the inhibitory effect of Ptch1 on Smo, which activates the Gli zinc-finger transcription factors; these factors control the transcription of Hh target genes, including Fox, Myc, Patched, Hhip, Snail, Nanog, Sox2, and cyclin D, which are involved in cell development, differentiation, epithelial-mesenchymal transition (EMT), and stem cell maintenance [18,19,20]
They observed the same effect of methiothepin on cells that had been rendered resistant to doxorubicin. These doxorubicin-resistant cells showed an increased level of Ptch1 expression, suggesting that their resistance to the treatment was due to Ptch1 upregulation. These results demonstrated that methiothepin strongly enhances the efficacy of doxorubicin on adrenocortical carcinoma (ACC) cells expressing Ptch1
Summary
Despite the major progress that has been made in biomedical research, and the development of novel therapeutic strategies, cancer is still among the dominant causes of death worldwide [1]. -triphosphate-binding-cassette (ABC) transporter superfamily transports toxins, sugars, amino acids, nucleotides, and metabolites out of cells [5], and protects cells from all living species against toxic molecules, including drugs. Since the discovery that the over-expression of ABC transporters in cancer cells can mediate resistance to anti-cancer drugs, research has been directed towards developing compounds that inhibit the efflux activity of these transporters, and thereby increase classical chemotherapy efficacy. Binding of Hh ligand to Ptch leads to its internalization and degradation This process relieves the inhibitory effect of Ptch on Smo, which activates the Gli zinc-finger transcription factors; these factors control the transcription of Hh target genes, including Fox, Myc, Patched, Hhip, Snail, Nanog, Sox, and cyclin D, which are involved in cell development, differentiation, epithelial-mesenchymal transition (EMT), and stem cell maintenance [18,19,20]. This is the case in particular for cells that exhibit resistance to chemotherapy, such as cancer stem cells or tumor-initiating cells [20]
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