Combination treatment with orlistat-containing nanoparticles and taxanes is synergistic and enhances microtubule stability in taxane-resistant prostate cancer cells

Joshua J. Souchek, Amanda L. Davis, Tanner K. Hill, Megan B. Holmes, Bowen Qi, Pankaj Singh, Steven J. Kridel, Aaron M Mohs

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1819-1830
Number of pages12
JournalMolecular cancer therapeutics
Volume16
Issue number9
DOIs
StatePublished - Sep 2017

Fingerprint

Taxoids
Microtubules
Nanoparticles
Prostatic Neoplasms
docetaxel
Therapeutics
Survival
orlistat
taxane
Anti-Obesity Agents
P-Glycoproteins
Cell Line
Fatty Acid Synthases
P-Glycoprotein
Tubulin
Choline
Paclitaxel
Lipase
Fluorescent Antibody Technique
Cell Survival

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Combination treatment with orlistat-containing nanoparticles and taxanes is synergistic and enhances microtubule stability in taxane-resistant prostate cancer cells. / Souchek, Joshua J.; Davis, Amanda L.; Hill, Tanner K.; Holmes, Megan B.; Qi, Bowen; Singh, Pankaj; Kridel, Steven J.; Mohs, Aaron M.

In: Molecular cancer therapeutics, Vol. 16, No. 9, 09.2017, p. 1819-1830.

Research output: Contribution to journalArticle

Souchek, Joshua J. ; Davis, Amanda L. ; Hill, Tanner K. ; Holmes, Megan B. ; Qi, Bowen ; Singh, Pankaj ; Kridel, Steven J. ; Mohs, Aaron M. / Combination treatment with orlistat-containing nanoparticles and taxanes is synergistic and enhances microtubule stability in taxane-resistant prostate cancer cells. In: Molecular cancer therapeutics. 2017 ; Vol. 16, No. 9. pp. 1819-1830.
@article{47e68552180a4e938c509e0b4c2f3511,
title = "Combination treatment with orlistat-containing nanoparticles and taxanes is synergistic and enhances microtubule stability in taxane-resistant prostate cancer cells",
abstract = "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.",
author = "Souchek, {Joshua J.} and Davis, {Amanda L.} and Hill, {Tanner K.} and Holmes, {Megan B.} and Bowen Qi and Pankaj Singh and Kridel, {Steven J.} and Mohs, {Aaron M}",
year = "2017",
month = "9",
doi = "10.1158/1535-7163.MCT-17-0013",
language = "English (US)",
volume = "16",
pages = "1819--1830",
journal = "Molecular Cancer Therapeutics",
issn = "1535-7163",
publisher = "American Association for Cancer Research Inc.",
number = "9",

}

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

AU - Kridel, Steven J.

AU - Mohs, Aaron M

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.

UR - http://www.scopus.com/inward/record.url?scp=85029430366&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85029430366&partnerID=8YFLogxK

U2 - 10.1158/1535-7163.MCT-17-0013

DO - 10.1158/1535-7163.MCT-17-0013

M3 - Article

C2 - 28615298

AN - SCOPUS:85029430366

VL - 16

SP - 1819

EP - 1830

JO - Molecular Cancer Therapeutics

JF - Molecular Cancer Therapeutics

SN - 1535-7163

IS - 9

ER -