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The SMAC mimetic LCL161 is a direct ABCB1/MDR1-ATPase activity modulator and BIRC5/Survivin expression down-regulator

Yung-Chieh Chang1, Sree Karani Kondapuram2, Tsung-Han Yang3

  • 1Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

Toxicology and Applied Pharmacology
|June 5, 2020
PubMed

Insights

LCL161 effectively treats multidrug-resistant cancers by inhibiting ABCB1 (P-gp) efflux and downregulating BIRC5 (Survivin), restoring sensitivity to chemotherapy and hormone therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Multidrug resistance (MDR) in cancers is often driven by ABCB1 (P-glycoprotein) and BIRC5 (Survivin) upregulation.
  • LCL161, a DIABLO/SMAC mimetic, is under investigation for solid tumors, but its mechanism in MDR cancers is unclear.
  • Therapeutic efficacy of LCL161 in ABCB1-overexpressing tumors remains to be determined.

Purpose of the Study:

  • To investigate the molecular mechanism of LCL161 in cancer cells.
  • To determine if LCL161 is effective against ABCB1-overexpressing multidrug-resistant tumors.
  • To explore LCL161's potential in combination therapy for drug-resistant cancers.

Main Methods:

  • Assessed LCL161 potency in cancer cell lines with varying ABCB1 and BIRC5 expression.
  • Investigated LCL161's direct effects on ABCB1-ATPase activity and drug efflux.
  • Analyzed LCL161's impact on intracellular ATP levels and BIRC5 expression.
  • Evaluated LCL161's ability to restore sensitivity to paclitaxel and tamoxifen in resistant cells.

Main Results:

  • LCL161 potency was unaffected by ABCB1 expression levels.
  • LCL161 directly inhibited ABCB1-ATPase activity and drug efflux at sub-cytotoxic concentrations.
  • LCL161 decreased intracellular ATP levels, partly via BIRC5 downregulation.
  • Co-treatment with LCL161 resensitized ABCB1-overexpressing cells to paclitaxel and tamoxifen-resistant cells to tamoxifen.

Conclusions:

  • LCL161 demonstrates potential for managing cancers with ABCB1 and BIRC5-mediated drug resistance.
  • LCL161 can overcome MDR by directly inhibiting P-gp and reducing ATP levels.
  • Findings support patient-specific clinical trial design for LCL161 in resistant cancers.
Keywords:
ABCB1ATPBIRC5LCL161Multidrug ResistanceSMAC

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