title: The Upregulation of PI3K/Akt and MAP Kinase Pathways is Associated with Resistance of Microtubule-Targeting Drugs in Prostate Cancer.
abstract: Resistance is a significant limitation to the effectiveness of cancer therapies. The PI3K/Akt and MAP kinase pathways play important roles in a variety of normal cellular processes and tumorigenesis. This study is designed to explore the relationship of these signaling pathways with multidrug resistance in prostate cancer (PCa). The PI3K/Akt and MAP kinase pathways were investigated utilizing paclitaxel resistant DU145-TxR PCa cells and their parental non-resistant DU145 cells to determine their relationship with resistance to paclitaxel and other anticancer drugs. Our results demonstrate that the PI3K/Akt and MAP kinase pathways are upregulated in DU145-TxR cells compared to the DU145 cells. Inactivating these pathways using the PI3K/Akt pathway inhibitor LY294002 or the MAP kinase pathway inhibitor PD98059 renders the DU145-TxR cells more sensitive to paclitaxel. We investigated the effects of these inhibitors on other anticancer drugs including docetaxel, vinblastine, doxorubicin, 10-Hydroxycamptothecin (10-HCPT) and cisplatin and find that both inhibitors induces DU145-TxR cells to be more sensitive only to the microtubule-targeting drugs (paclitaxel, docetaxel and vinblastine). Furthermore, the treatment with these inhibitors induces cleaved-PARP production in DU145-TxR cells, suggesting that apoptosis induction might be one of the mechanisms for the reversal of drug resistance. In conclusion, the PI3K/Akt and MAP kinase pathways are associated with resistance to multiple chemotherapeutic drugs. Inactivating these pathways renders these PCa cells more sensitive to microtubule-targeting drugs such as paclitaxel, docetaxel and vinblastine. Combination therapies with novel inhibitors of these two signaling pathways potentially represents a more effective treatment for drug resistant PCa.
authors: The James Buchanan Brady Urological Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287.
authors: Zhi
authors: Z
authors: Liu
authors: The James Buchanan Brady Urological Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287.
authors: Guangjing
authors: G
authors: Zhu
authors: GTx Inc., Memphis, Tennessee, 38103.
authors: Robert H
authors: RH
authors: Getzenberg
authors: The James Buchanan Brady Urological Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287.
authors: Robert W
authors: RW
authors: Veltri
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D050257:Tubulin Modulators / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D002867:Chromones; D005419:Flavonoids; D009025:Morpholines; D050257:Tubulin Modulators; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
keywords: MAPK; MULTIDRUG RESISTANCE; PARP; PI3K/Akt; PROSTATE CANCER