Renal human organic anion transporter 3 increases the susceptibility of lymphoma cells to bendamustine uptake

Abstract

Chronic lymphatic leukemia (CLL) is often associated with nephritic syndrome. Effective treatment of CLL by chlorambucil and bendamustine leads to the restoration of renal function. In this contribution, we sought to elucidate the impact of organic anion transporters (OATs) on the uptake of bendamustine and chlorambucil as a probable reason for the superior efficacy of bendamustine over chlorambucil in the treatment of CLL. We examined the effects of structural analogs of p-aminohippurate (PAH), melphalan, chlorambucil, and bendamustine, on OAT1-mediated [(3)H]PAH uptake and OAT3- and OAT4-mediated [(3)H]estrone sulfate (ES) uptake in stably transfected human embryonic kidney-293 cells. Melphalan had no significant inhibitory effect on any OAT, whereas chlorambucil reduced OAT1-, OAT3-, and OAT4-mediated uptake of PAH or ES down to 14.6%, 16.3%, and 66.0% of control, respectively. Bendamustine inhibited only OAT3-mediated ES uptake, which was reduced down to 14.3% of control cells, suggesting that it interacts exclusively with OAT3. The IC50 value for OAT3 was calculated to be 0.8 μM. Real-time PCR experiments demonstrated a high expression of OAT3 in lymphoma cell lines as well as primary CLL cells. OAT3-mediated accumulation of bendamustine was associated with reduced cell proliferation and an increased rate of apoptosis. We conclude that the high efficacy of bendamustine in treating CLL might be partly contributed to the expression of OAT3 in lymphoma cells and the high affinity of bendamustine for this transporter.

Functional and Pharmacological Comparison of Human, Mouse, and Rat Organic Cation Transporter 1 toward Drug and Pesticide Interaction

“…Drug-induced cis-stimulation of the reference substrate uptake was observed previously for various influx as well as for efflux transporters and numerous compounds. Hagos et al demonstrated 24% to 86% stimulation of OAT3 (SLC22A8) as well as OAT4 (SLC22A11)-mediated estrone sulfate uptake by melphalan, respectively [ 45 ]. Irinotecan caused 93% stimulation of estrone sulfate uptake by OATP1B1 (SLCO1B1), as reported by Marada et al (2015) [ 46 ].…”

CD69 expression potentially predicts response to bendamustine and its modulation by ibrutinib or idelalisib enhances cytotoxic effect in chronic lymphocytic leukemia

“…Moreover, bendamustine engages cell death through both apoptotic and non-apoptotic pathways, thereby retaining activity even in cells with dysfunctional apoptotic machinery [ 24 ]. Recently, it has been reported that some membrane transporters might also contribute to the cytotoxic effect of bendamustine [ 25 , 26 ].…”

Exosomes secreted from cancer-associated fibroblasts elicit anti-pyrimidine drug resistance through modulation of its transporter in malignant lymphoma

“…In the presence of co-culture with CAFs, the induction of resistance to gemcitabine, cytarabine, and bendamustine was observed, though resistance to bendamustine was not induced in the presence of exosomes from CAFs. Considering that the uptake of bendamustine into lymphoma cells is thought to be through human organic cation transporter 1 (OCT1) and human organic anion transporter 3 (OAT3) [ 29 , 30 ], the difference in drug transporters between anti-pyrimidine drugs and bendamustine might have caused this discrepancy. In addition, our finding that resistance to bendamustine was not observed in the presence of exosomes suggests that drug resistance by CAFs is induced by varying mechanisms.…”