Immuno-oncology agent IPI-549 is a modulator of P-glycoprotein (P-gp, MDR1, ABCB1)-mediated multidrug resistance (MDR) in cancer: In vitro and in vivo

Albert A. De Vera, Pranav Gupta, Zining Lei, Dan Liao, Silpa Narayanan, Qiuxu Teng, Sandra E. Reznik, Zhe Sheng Chen

Research output: Contribution to journalArticle

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Abstract

Phosphoinositide 3-kinase gamma isoform (PI3Kγ) plays a critical role in myeloid-derived cells of the immunosuppressive tumor microenvironment. IPI-549, a recently discovered small molecule selective PI3Kγ inhibitor, is currently under immuno-oncology clinical trials in combination with nivolumab, an anti-PD-1 monoclonal antibody immune checkpoint blocker. The purpose of this study is to investigate whether IPI-549 could reverse P-glycoprotein (P-gp)-mediated MDR when combined with chemotherapeutic substrates of P-gp. Cytotoxicity assays showed that IPI-549 reverses P-gp-mediated MDR in SW620/Ad300 and LLC-PK-MDR1 cells. IPI-549 increases the amount of intracellular paclitaxel and inhibits the efflux of paclitaxel out of SW620/Ad300 cells. ABCB1-ATPase assay showed that IPI-549 stimulates the activity of ABCB1-ATPase. IPI-549 does not alter the expression and does not affect the subcellular localization of P-gp in SW620/Ad300 cells. The combination of IPI-549 with paclitaxel showed that IPI-549 potentiates the anti-tumor effects of paclitaxel in P-gp-overexpressing MDR SW620/Ad300 xenograft tumors. With clinical trials beginning to add newly approved immune checkpoint-based immunotherapy into standard-of-care immunogenic chemotherapy to improve patient outcomes, our findings support the rationale of adding IPI-549 to both the chemotherapeutic and immunotherapeutic aspects of cancer combination treatment strategies.

Original languageEnglish (US)
Pages (from-to)91-103
Number of pages13
JournalCancer Letters
Volume442
DOIs
StatePublished - Feb 1 2019

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Multiple Drug Resistance
P-Glycoprotein
Paclitaxel
1-Phosphatidylinositol 4-Kinase
Neoplasms
Adenosine Triphosphatases
Protein Isoforms
Clinical Trials
Tumor Microenvironment
Myeloid Cells
Standard of Care
Immunosuppressive Agents
Heterografts
Immunotherapy
Monoclonal Antibodies
In Vitro Techniques
Drug Therapy

Keywords

  • ABCB1 transporter
  • Combination chemotherapy
  • Immune checkpoint
  • IPI-549
  • Multidrug resistance
  • P-glycoprotein

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Immuno-oncology agent IPI-549 is a modulator of P-glycoprotein (P-gp, MDR1, ABCB1)-mediated multidrug resistance (MDR) in cancer : In vitro and in vivo. / De Vera, Albert A.; Gupta, Pranav; Lei, Zining; Liao, Dan; Narayanan, Silpa; Teng, Qiuxu; Reznik, Sandra E.; Chen, Zhe Sheng.

In: Cancer Letters, Vol. 442, 01.02.2019, p. 91-103.

Research output: Contribution to journalArticle

De Vera, Albert A. ; Gupta, Pranav ; Lei, Zining ; Liao, Dan ; Narayanan, Silpa ; Teng, Qiuxu ; Reznik, Sandra E. ; Chen, Zhe Sheng. / Immuno-oncology agent IPI-549 is a modulator of P-glycoprotein (P-gp, MDR1, ABCB1)-mediated multidrug resistance (MDR) in cancer : In vitro and in vivo. In: Cancer Letters. 2019 ; Vol. 442. pp. 91-103.
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AB - Phosphoinositide 3-kinase gamma isoform (PI3Kγ) plays a critical role in myeloid-derived cells of the immunosuppressive tumor microenvironment. IPI-549, a recently discovered small molecule selective PI3Kγ inhibitor, is currently under immuno-oncology clinical trials in combination with nivolumab, an anti-PD-1 monoclonal antibody immune checkpoint blocker. The purpose of this study is to investigate whether IPI-549 could reverse P-glycoprotein (P-gp)-mediated MDR when combined with chemotherapeutic substrates of P-gp. Cytotoxicity assays showed that IPI-549 reverses P-gp-mediated MDR in SW620/Ad300 and LLC-PK-MDR1 cells. IPI-549 increases the amount of intracellular paclitaxel and inhibits the efflux of paclitaxel out of SW620/Ad300 cells. ABCB1-ATPase assay showed that IPI-549 stimulates the activity of ABCB1-ATPase. IPI-549 does not alter the expression and does not affect the subcellular localization of P-gp in SW620/Ad300 cells. The combination of IPI-549 with paclitaxel showed that IPI-549 potentiates the anti-tumor effects of paclitaxel in P-gp-overexpressing MDR SW620/Ad300 xenograft tumors. With clinical trials beginning to add newly approved immune checkpoint-based immunotherapy into standard-of-care immunogenic chemotherapy to improve patient outcomes, our findings support the rationale of adding IPI-549 to both the chemotherapeutic and immunotherapeutic aspects of cancer combination treatment strategies.

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