The growing evidence for targeting P-glycoprotein in lysosomes to overcome resistance

References

• 1. Sedlakova I, Lavo J, Caltova K et al. Clinical significance of the resistance proteins LRP, Pgp, MRP1, MRP3, and MRP5 in epithelial ovarian cancer. Int. J. Gynecol. Cancer 25(2), 236–243 (2015).
  MedlineGoogle Scholar
• 2. Zeng DF, Zhang J, Zhu LD et al. Analysis of drug resistance-associated proteins expressions of patients with the recurrent of acute leukemia via protein microarray technology. Eur. Rev. Med. Pharmacol. Sci. 18(4), 537–543 (2014).
  MedlineGoogle Scholar
• 3. Matsuo K, Eno ML, Ahn EH et al. Multidrug resistance gene (MDR-1) and risk of brain metastasis in epithelial ovarian, fallopian tube, and peritoneal cancer. Am. J. Clin. Oncol. 34(5), 488–493 (2011).
  Medline CASGoogle Scholar
• 4. Stefan SM. Multi-target ABC transporter modulators: what next and where to go? Future Med. Chem. 11(18), 2353–2358 (2019).
  CASGoogle Scholar
• 5. Jansson PJ, Yamagishi T, Arvind A et al. Di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT) overcomes multidrug resistance by a novel mechanism involving hijacking lysosomal P-glycoprotein (Pgp). J. Biol. Chem. 290(15), 958–9603 (2015).
  Google Scholar
• 6. Seebacher NA, Richardson DR, Jansson PJ. A mechanism for overcoming P-glycoprotein-mediated drug resistance: novel combination therapy that releases stored doxorubicin from lysosomes via lysosomal permeabilization using DP44mT or DpC. Cell Death Dis. 7(12), e2510 (2016).
  Medline CASGoogle Scholar
• 7. Seebacher N, Lane DJR, Richardson DR, Jansson PJ. Turning the gun on cancer: utilizing lysosomal P-glycoprotein as a new strategy to overcome multi-drug resistance. Free Radic. Biol. Med. 96, 432–445 (2016).
  Medline CASGoogle Scholar
• 8. Fu D. Where is it and how does it get there – intracellular localization and traffic of P-glycoprotein. Front. Oncol. 3, 321, 1–5 (2013).
  MedlineGoogle Scholar
• 9. Fu D, Bebawy M, Kable EPW, Roufogalis BD. Dynamic and intracellular trafficking of P-glycoprotein-EGFP fusion protein: implications in multidrug resistance in cancer. Int. J. Cancer 109(2), 174–181 (2004).
  Medline CASGoogle Scholar
• 10. Fu D, Roufogalis BD. Actin disruption inhibits endosomal traffic of P-glycoprotein-EGFP and resistance to daunorubicin accumulation. Am. J. Physiol. Cell. Physiol. 292(4), C1543–C1552 (2007).
  Medline CASGoogle Scholar
• 11. Yamagishi T, Sahni S, Sharp DM, Arvind A, Jansson PJ, Richardson DR. P-glycoprotein mediated drug resistance via a novel mechanism involving lysosomal sequestration. J. Biol. Chem. 288(44), 31761–31771 (2013).
  Medline CASGoogle Scholar
• 12. Seebacher N, Lane DJR, Jansson PJ, Richardson DR. Glucose modulation induces lysosome formation and increases lysosomotropic drug sequestration via the P-glycoprotein drug transporter. J. Biol. Chem. 291(8), 3796–3820 (2016).
  Medline CASGoogle Scholar
• 13. Noack A, Gericke B, von Köckritz-Blickwede M et al. Mechanism of drug extrusion by brain endothelial cells via lysosomal drug trapping and disposal by neutrophils. Proc. Natl Acad. Sci. USA 115(41), E9590–E9599 (2018).
  Medline CASGoogle Scholar
• 14. Zhitomirsky B, Assaraf YG. Lysosomes as mediators of drug resistance in cancer. Drug Resist. Updat. 24, 23–33 (2016).
  MedlineGoogle Scholar
• 15. Al-Akra L, Bae DH, Sahni S et al. Tumor stressors induce two mechanisms of intracellular P-glycoprotein-mediated resistance that are overcome by lysosomal-targeted thiosemicarbazones. J. Biol. Chem. 293(10), 3562–3587 (2018).
  Medline CASGoogle Scholar
• 16. Seebacher NA, Richardson DR, Jansson PJ. Glucose modulation induces reactive oxygen species and increases P-glycoprotein-mediated multidrug resistance to chemotherapeutics. Br. J. Pharmacol. 172(10), 2557–2572 (2015).
  Medline CASGoogle Scholar
• 17. Halaby R. Influence of lysosomal sequestration on multidrug resistance in cancer cells. Cancer Drug Resist. 2(1), 31–42 (2019).
  Google Scholar
• 18. Duvvuri M, Krisae JP. Intracellular drug sequestration events associated with the emergence of multidrug resistance: a mechanistic review. Front. Biosci. 10, 1499–1509 (2005).
  Medline CASGoogle Scholar
• 19. Groth-Pedersen L, Jäättelä M. Combating apoptosis and multidrug resistant cancers by targeting lysosomes. Cancer Lett. 332(2), 265–274 (2013).
  Medline CASGoogle Scholar
• 20. Noack A, Mpacl S, Buettner M, Naim HY, Löscher W. Intercellular transfer of P-glycoprotein in human blood–brain barrier endothelial cells is increased by histone deacetylase inhibitors. Sci. Rep. 6, 29253 (2016).
  Medline CASGoogle Scholar
• 21. Lovejoy DB, Jansson PJ, Brunk UT, Wong J, Ponka P, Richardson DR. Antitumor activity of metal-chelating compound Dp44mT is mediated by formation of redox-active copper complex that accumulates in lysosomes. Cancer Res. 71(17), 5871–5880 (2011).
  Medline CASGoogle Scholar
• 22. Richardson DR, Kalinowski DS, Richardson V, Sharpe PC, Lovejoy DB, Islam M. 2-Acetylpyridine thiosemicarbazones are potent iron chelators and antiproliferative agents: redox activity, iron complexation and characterization of their antitumor activity. J. Med. Chem. 52(5), 1459–1470 (2009).
  Medline CASGoogle Scholar
• 23. Stacy AE, Palanimuthu D, Bernhardt PV, Kalinowski DS, Jansson PJ, Richardson DR. Structure–activity relationships of di-2-pyridylketone, 2-benzoylpyridine, and 2-acetylpyridine thiosemicarbazones for overcoming P-gp-mediated drug resistance. J. Med. Chem. 59(18), 8601–8620 (2016).
  Medline CASGoogle Scholar
• 24. Jansson PJ, Sharpe PC, Bernhardt PV et al. Novel thiosemicarbazones of the Apt and DpT series and their copper complexes: identification of pronounced redox activity and characterization of their antitumor activity. J. Med. Chem. 53(15), 5759–5769 (2010).
  Medline CASGoogle Scholar
• 25. Klionsky DJ, Abdelmohsen K, Abe A et al. Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12(1), 1–222 (2016).
  MedlineGoogle Scholar
• 26. Jansson PJ, Hawkins CL, Lovejoy DB, Richardson DR. The iron complex of Dp44mT is redox-active and induces hydroxyl radical formation: an EPR study. J. Inorg. Biochem. 104(11), 1224–1228 (2010).
  Medline CASGoogle Scholar
• 27. Gutierrez EM, Seebacher NA, Arzuman L et al. Lysosomal membrane stability plays a major role in the cytotoxic activity of the anti-proliferative agent, di-2-pyridylketone 4,4,dimethyl-3-thiosemicarbazone (Dp44mT). Biochim. Biophys. Acta 1863(7A), 1665–1681 (2016).
  Medline CASGoogle Scholar
• 28. Yuan J, Lovejoy DB, Richardson DR. Novel di-2-pyridyl-derived iron chelators with marked and selective antitumor activity: in vitro and in vivo assessment. Blood 104(5), 1450–1458 (2004).
  Medline CASGoogle Scholar
• 29. Shi L, Ito F, Wang Y et al. Non-thermal plasma induces a stress response in mesothelioma cells resulting in increased endocytosis, lysosome biogenesis and autophagy. Free Radic. Biol. Med. 108, 904–917 (2017).
  Medline CASGoogle Scholar
• 30. Heffeter P, Paper VFS, Enyedy EA et al. Anticancer thiosemicarbazones: chemical properties, interaction with iron metabolism, and resistance development. Antioxid. Redox. Signal. 30(8), 1062–1082 (2019).
  Medline CASGoogle Scholar
• 31. Rajagopal A, Simon SM. Subcellular localization and activity of multidrug resistance proteins. Mol. Biol. Cell 14(8), 3389–3399 (2003).
  Medline CASGoogle Scholar
• 32. Hummel I, Klappe K, Ercan C, Kok JW. Multidrug resistance-related protein 1 (MRP1) function and localization depend on cortical actin. Mol. Pharmacol. 79(2), 229–240 (2011).
  Medline CASGoogle Scholar