TY - JOUR
T1 - Combination treatment with orlistat-containing nanoparticles and taxanes is synergistic and enhances microtubule stability in taxane-resistant prostate cancer cells
AU - Souchek, Joshua J.
AU - Davis, Amanda L.
AU - Hill, Tanner K.
AU - Holmes, Megan B.
AU - Qi, Bowen
AU - Singh, Pankaj K.
AU - Kridel, Steven J.
AU - Mohs, Aaron M.
N1 - Funding Information:
This work was supported by National Institute of General Medical Sciences (P20 GM103480), the National Cancer Institute (R01 CA163649, R01 CA210439, R01 CA216853, and 2P50 CA127297), the Fred and Pamela Buffett Cancer Center at UNMC (P30 CA036727), and the Comprehensive Cancer Center of Wake Forest University (P30 CA012197).
Publisher Copyright:
©2017 AACR.
PY - 2017/9
Y1 - 2017/9
N2 - Taxane-based therapy provides a survival benefit in patients with metastatic prostate cancer, yet the median survival is less than 20 months in this setting due in part to taxane-associated resistance. Innovative strategies are required to overcome chemoresistance for improved patient survival. Here, NanoOrl, a new experimental nanoparticle formulation of the FDA-approved drug, orlistat, was investigated for its cytotoxicity in taxane-resistant prostate cancer utilizing two established taxane-resistant (TxR) cell lines. Orlistat is a weight loss drug that inhibits gastric lipases, but is also a potent inhibitor of fatty acid synthase (FASN), which is overexpressed in many types of cancer. NanoOrl was also investigated for its potential to synergize with taxanes in TxR cell lines. Both orlistat and NanoOrl synergistically inhibited cell viability when combined with paclitaxel, docetaxel, and cabazitaxel in PC3-TxR and DU145-TxR cells, yet these combinations were also additive in parental lines. We observed synergistic levels of apoptosis in TxR cells treated with NanoOrl and docetaxel in combination. Mechanistically, the synergy between orlistat and taxanes was independent of effects on the P-glycoprotein multidrug resistance protein, as determined by an efflux activity assay. On the other hand, immunoblot and immunofluorescence staining with an anti-detyrosinated tubulin antibody demonstrated that enhanced microtubule stability was induced by combined NanoOrl and docetaxel treatment in TxR cells. Furthermore, TxR cells exhibited higher lipid synthesis, as demonstrated by 14C-choline incorporation that was abrogated by NanoOrl. These results provide a strong rationale to assess the translational potential of NanoOrl to overcome taxane resistance.
AB - Taxane-based therapy provides a survival benefit in patients with metastatic prostate cancer, yet the median survival is less than 20 months in this setting due in part to taxane-associated resistance. Innovative strategies are required to overcome chemoresistance for improved patient survival. Here, NanoOrl, a new experimental nanoparticle formulation of the FDA-approved drug, orlistat, was investigated for its cytotoxicity in taxane-resistant prostate cancer utilizing two established taxane-resistant (TxR) cell lines. Orlistat is a weight loss drug that inhibits gastric lipases, but is also a potent inhibitor of fatty acid synthase (FASN), which is overexpressed in many types of cancer. NanoOrl was also investigated for its potential to synergize with taxanes in TxR cell lines. Both orlistat and NanoOrl synergistically inhibited cell viability when combined with paclitaxel, docetaxel, and cabazitaxel in PC3-TxR and DU145-TxR cells, yet these combinations were also additive in parental lines. We observed synergistic levels of apoptosis in TxR cells treated with NanoOrl and docetaxel in combination. Mechanistically, the synergy between orlistat and taxanes was independent of effects on the P-glycoprotein multidrug resistance protein, as determined by an efflux activity assay. On the other hand, immunoblot and immunofluorescence staining with an anti-detyrosinated tubulin antibody demonstrated that enhanced microtubule stability was induced by combined NanoOrl and docetaxel treatment in TxR cells. Furthermore, TxR cells exhibited higher lipid synthesis, as demonstrated by 14C-choline incorporation that was abrogated by NanoOrl. These results provide a strong rationale to assess the translational potential of NanoOrl to overcome taxane resistance.
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U2 - 10.1158/1535-7163.MCT-17-0013
DO - 10.1158/1535-7163.MCT-17-0013
M3 - Article
C2 - 28615298
AN - SCOPUS:85029430366
SN - 1535-7163
VL - 16
SP - 1819
EP - 1830
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
IS - 9
ER -