Inhibition of OCTN2-Mediated Transport of Carnitine by Etoposide

  title={Inhibition of OCTN2-Mediated Transport of Carnitine by Etoposide},
  author={Chaoxin Hu and Cynthia S. Lancaster and Zhili Zuo and Shuiying Hu and Zhaoyuan Chen and Jeffrey E. Rubnitz and Sharyn D. Baker and Alex Sparreboom},
  journal={Molecular Cancer Therapeutics},
  pages={921 - 929}
OCTN2 is a bifunctional transporter that reabsorbs filtered carnitine in a sodium-dependent manner and secretes organic cations into urine as a proton antiport mechanism. We hypothesized that inhibition of OCTN2 by anticancer drugs can influence carnitine resorption. OCTN2-mediated transport inhibition by anticancer drugs was assessed using cells transfected with human OCTN2 (hOCTN2) or mouse Octn2 (mOctn2). Excretion of carnitine and acetylcarnitine was measured in urine collected from mice… 

Figures and Tables from this paper

The human organic cation transporter OCT1 mediates high affinity uptake of the anticancer drug daunorubicin

Using the high-grade serous ovarian cancer cell line TOV2223G, it is shown that OCT1 mediated the high affinity uptake of daunorubicin into the cells, and that micromolar amounts of choline completely abolished the drug entry.

SLC22A5 (OCTN2) Carnitine Transporter—Indispensable for Cell Metabolism, a Jekyll and Hyde of Human Cancer

SLC22A5 expression is altered in many types of cancer, giving an advantage to some of them by supplying carnitine for β-oxidation, thus providing an alternative to glucose source of energy for growth and proliferation.

Recent advances in drug delivery via the organic cation/carnitine transporter 2 (OCTN2/SLC22A5)

This transporter has great potential to be utilized as a target for drug delivery to improve oral absorption of drugs in the intestinal tract and has potential to facilitate the transfer of drugs across the biological barriers such as the blood-brain barrier, blood-retinal barrier, and maternal-fetal barrier.

OCTN1 Is a High-Affinity Carrier of Nucleoside Analogues.

Through transcriptomic profiling, it is determined that low expression of the ergothioneine transporter OCTN1 (SLC22A4; ETT) strongly predicts poor event-free survival and overall survival in multiple cohorts of AML patients receiving treatment with the cytidine nucleoside analogue cytarabine.

OCTN Cation Transporters in Health and Disease

Proteoliposomes represent a promising experimental tool suitable for large-scale molecular screening of interactions of OCTNs with chemicals regarding human health, thus representing useful pharmacological targets.

Hepatocellular Shuttling and Recirculation of Sorafenib-Glucuronide Is Dependent on Abcc2, Abcc3, and Oatp1a/1b.

The results suggest broad relevance of a hepatocyte shuttling process known as "hepatocyte hopping"-a novel concept in clinical pharmacology-for detoxification of targeted cancer drugs that undergo hepatic glucuronidation, such as sorafenib.

Glioma cells survival depends both on fatty acid oxidation and on functional carnitine transport by SLC22A5

It is shown that SLC22A5 is up‐regulated in glioma cells and that they vary in the amount of SLC 22A5 in the plasma membrane, as well as that CPT1 and SLC23A5 might be possible drug targets.

Organic Cation Transporters in Health and Disease

A hypothesis about the molecular mechanism of polyspecific substrate recognition by OCTs is presented that is based on functional studies and mutagenesis experiments in OCT1 and OCT2 and provides a framework to imagine how observed complex drug–drug interactions at OCTs arise.



Cisplatin-Induced Downregulation of OCTN2 Affects Carnitine Wasting

Cisplatin did not directly inhibit the transport of carnitine by Octn2 but downregulated multiple target genes of the transcription factor peroxisome proliferator activated receptor α in the kidney of wild-type mice that were absent in Oct1/2(−/−) mice, suggesting that tubular transport of cisplatin is a prerequisite for this phenomenon.

Pharmacological manipulation of L-carnitine transport into L6 cells with stable overexpression of human OCTN2

Overexpressed hOCTN2 in L6 cells and characterized the structural requirements of substances acting as human OCTN2 (hOCTn2) inhibitors revealed increased expression of hO CTN2 on the mRNA, protein and functional levels.

β-Lactam Antibiotics as Substrates for OCTN2, an Organic Cation/Carnitine Transporter*

OCTN2 plays a crucial role in the pharmacokinetics and therapeutic efficacy of certain β-lactam antibiotics such as cephaloridine and that cep Haloridine-induced carnitine deficiency is likely to be due to inhibition of carnitines reabsorption in the kidney.

The Carnitine Transporter SLC22A5 Is Not a General Drug Transporter, but It Efficiently Translocates Mildronate

The results establish that OCTN2 is a key target of the cardioprotective agent Mildronate because it controls, as integral protein of the plasma membrane, cellular entry of mildronate and enables efficient access to intracellular targets.

Molecular and Functional Characterization of Organic Cation/Carnitine Transporter Family in Mice*

OCTN3 is unique in its limited tissue distribution and Na+-independent carnitine transport, whereas OCTN1 efficiently transported TEA with minimal expression of carn itine transport activity and may have a different role from other members of the OCTN family.

Novel Inhibitors of Human Organic Cation/Carnitine Transporter (hOCTN2) via Computational Modeling and In Vitro Testing

A combined pharmacophore and in vitro approach found new, structurally diverse inhibitors for hOCTN2 that may possibly cause clinical significant toxicity such as rhabdomyolysis.

Functional regions of organic cation/carnitine transporter OCTN2 (SLC22A5): roles in carnitine recognition.

It is proposed that sodium-dependent affinity for carnitine is dependent on sodium recognition by these critical amino acids in hOCTN2, whereas carnitines transport by OCTN2 requires functional linkage between TMD1-7 and TMD11.

Organic Cation/Carnitine Transporter OCTN2 (Slc22a5) Is Responsible for Carnitine Transport across Apical Membranes of Small Intestinal Epithelial Cells in Mouse

Findings indicate that OCTN2 is predominantly responsible for the uptake of carnitine from the apical surface of mouse small intestinal epithelial cells, and it may therefore be a promising target for oral delivery of therapeutic agents that are OCTn2 substrates.

Mutations in Novel Organic Cation Transporter (OCTN2), an Organic Cation/Carnitine Transporter, with Differential Effects on the Organic Cation Transport Function and the Carnitine Transport Function*

Findings are of clinical relevance to patients with primary carnitine deficiency because whereas each and every mutation in these patients is expected to result in the loss of the carnitines transport function, all of these mutations may not interfere with the organic cation transport function.

Species Difference in Intestinal Absorption Mechanism of Etoposide and Digoxin between Cynomolgus Monkey and Rat

Low bioavailability of etoposide in monkeys is due to poor intestinal uptake resulting from low influx from the apical side, rather than secretion via P-gp, and apical uptake is rate-limiting.