[Mechanisms for resistance to anticancer agents and the reversal of the resistance]

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Evaluating the Effectiveness of Cancer Drug Sensitization In Vitro and In Vivo
09:19

Evaluating the Effectiveness of Cancer Drug Sensitization In Vitro and In Vivo

Published on: February 6, 2015

S Akiyama1, Z S Chen, M Kitazono

  • 1Institute for Cancer Research, Faculty of Medicine, Kagoshima University.

Human Cell
|March 1, 2000
PubMed

Insights

Lung resistance related protein (LRP) contributes to multidrug resistance (MDR) by facilitating drug efflux from the nucleus. Inhibiting LRP expression or function can reverse MDR, offering potential therapeutic strategies.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Pharmacology

Background:

  • Multidrug resistance (MDR) is often mediated by efflux pumps like P-glycoprotein (Pgp) and multidrug resistance-associated protein 1 (MRP1).
  • Lung resistance related protein (LRP) is implicated in MDR, but its precise role remains under investigation.
  • Canalicular multispecific organic anion transporter (cMOAT) is homologous to MRP1 and its involvement in drug resistance is hypothesized.

Purpose of the Study:

  • To investigate the role of cMOAT in drug resistance.
  • To elucidate the mechanism by which LRP confers multidrug resistance.
  • To assess the potential of LRP-specific interventions in reversing MDR.

Main Methods:

  • Transfection of LLC-PK1 cells with human cMOAT cDNA to create LLC/cMOAT-1 cells.
  • Treatment of human colorectal carcinoma SW-620 cells with sodium butyrate (NaB) to induce LRP expression.
  • Utilizing LRP-specific ribozymes to inhibit NaB-induced LRP expression.
  • Assessing drug accumulation and localization (e.g., Adriamycin) in treated and untreated cells.
  • Employing polyclonal antibodies against LRP to study drug efflux.

Main Results:

  • LLC/cMOAT-1 cells exhibited increased resistance to vincristine (VCR), SN-38, and cisplatin, which was reversed by MDR-reversing agents.
  • NaB treatment induced LRP in SW-620 cells, conferring resistance to Adriamycin (ADM), VCR, VP-16, gramicidin D, and taxol.
  • LRP-specific ribozymes abolished the MDR phenotype in NaB-treated cells.
  • ADM accumulation was not reduced in NaB-treated cells, suggesting non-ATP-dependent transporter involvement.
  • ADM localized to the cytoplasm in NaB-treated cells, contrasting with nuclear localization in untreated cells.
  • Enhanced ADM efflux from nuclei of NaB-treated cells was observed, and this efflux was inhibited by anti-LRP antibodies.

Conclusions:

  • cMOAT mediates resistance to VCR, SN-38, and cisplatin.
  • LRP plays a significant role in conferring resistance to a range of chemotherapeutic agents, including ADM, VCR, VP-16, taxol, and gramicidin D.
  • LRP is involved in the nuclear-to-cytoplasmic transport of ADM, contributing to MDR.
  • Targeting LRP presents a potential strategy for overcoming multidrug resistance in cancer therapy.

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