Uptake Transporters of the SLC21, SLC22A, and SLC15A Families in Anticancer Therapy—Modulators of Cellular Entry or Pharmacokinetics?

Abstract

Solute carrier transporters comprise a large family of uptake transporters involved in the transmembrane transport of a wide array of endogenous substrates such as hormones, nutrients, and metabolites as well as of clinically important drugs. Several cancer therapeutics, ranging from chemotherapeutics such as topoisomerase inhibitors, DNA-intercalating drugs, and microtubule binders to targeted therapeutics such as tyrosine kinase inhibitors are substrates of solute carrier (SLC) transporters. Given that SLC transporters are expressed both in organs pivotal to drug absorption, distribution, metabolism, and elimination and in tumors, these transporters constitute determinants of cellular drug accumulation influencing intracellular drug concentration required for efficacy of the cancer treatment in tumor cells. In this review, we explore the current understanding of members of three SLC families, namely SLC21 (organic anion transporting polypeptides, OATPs), SLC22A (organic cation transporters, OCTs; organic cation/carnitine transporters, OCTNs; and organic anion transporters OATs), and SLC15A (peptide transporters, PEPTs) in the etiology of cancer, in transport of chemotherapeutic drugs, and their influence on efficacy or toxicity of pharmacotherapy. We further explore the idea to exploit the function of SLC transporters to enhance cancer cell accumulation of chemotherapeutics, which would be expected to reduce toxic side effects in healthy tissue and to improve efficacy.

Identification of Metabolism-Associated Prostate Cancer Subtypes and Construction of a Prognostic Risk Model

“…This indicates that C1 may exhibit high sensitivity to anti-androgenic therapy. With a high expression of immune checkpoints and significant features of immune cell infiltration, C2 tumors may benefit more from immune-targeted therapy, whereas C3, with an active status of specific drug metabolism pathways, may facilitate the development of tolerance to traditional chemotherapy (65). In the drug sensitivity analysis of the risk model, our study suggests that patients with low-risk scores may benefit more from anti-PD-1 treatment, and this is consistent with C2 being more suitable for immune target therapy.…”

Expression status of p53 and organic cation transporter 1 is correlated with poor response to preoperative chemotherapy in esophageal squamous cell carcinoma

“…The effectiveness of chemotherapy is also dependent on the intracellular accumulation of anticancer drugs. Cellular uptake of anticancer drugs is mediated by facilitated transport systems via solute carrier (SLC) transporters, suggesting that the expression of SLC transporters may help to predict the response to chemotherapy [ 15 – 18 ]. The organic cation transporters (OCTs) of the SLC22A family consist of three isoforms, OCT1, OCT2, and OCT3, which mediate the uptake transport of various organic cations including endogenous compounds, xenobiotics, and anticancer drugs [ 15 – 18 ].…”

“…Cellular uptake of anticancer drugs is mediated by facilitated transport systems via solute carrier (SLC) transporters, suggesting that the expression of SLC transporters may help to predict the response to chemotherapy [ 15 – 18 ]. The organic cation transporters (OCTs) of the SLC22A family consist of three isoforms, OCT1, OCT2, and OCT3, which mediate the uptake transport of various organic cations including endogenous compounds, xenobiotics, and anticancer drugs [ 15 – 18 ]. An in vitro study demonstrated that transfection of OCT1 increased the accumulation and cytotoxicity of CDDP in human embryonic kidney cells [ 19 ], although another study presented results that were negative for the involvement of OCT1 in the accumulation and cytotoxicity of CDDP [ 20 ].…”

SLC34A2 Up-regulation And SLC4A4 Down-regulation Correlates With Invasion, Metastasis, And The MAPK Signaling Pathway In Papillary Thyroid Carcinomas

“…These transporters utilize an electrochemical or ion gradient to facilitate the exchange of various substances, including endogenous or xenobiotic compounds as well as molecules across the biological membranes, such as sugars, nucleotides, amino acids, nutrients, and drugs 5 , 6 . Recently, a several studies have highlighted that SLC transporters might play a critical role in the initiation, progression, metastasis, and prognosis of human carcinoma 7 , 8 . For instance, Kikuchi et al 9 found that up-regulated SLC37A1 was significantly associated with the venous invasion and liver metastasis of colorectal cancer.…”