Novel inhibitors of breast cancer resistance protein (BCRP, ABCG2) among marketed drugs

Deng, Feng; Sjöstedt, Noora; Santo, Mariangela; Neuvonen, Mikko; Niemi, Mikko; Kidron, Heidi

doi:10.1016/j.ejps.2022.106362

Cited by 15 publications

(8 citation statements)

References 69 publications

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“…Although numerous ABCG2 inhibitors have been developed, there have been no successful clinical trials published in the re-sensitization of ABCG2-mediated chemoresistance as of yet ( 46 ). Additionally, the adverse drug interactions and side effects of these ABCG2 inhibitors ( 47 , 48 ) and the influence of the TME, such as ARM, may be another concern affecting the function of ABCG2 transporters and subsequently influencing the application of the inhibitors. It has thus been suggested that any therapeutic strategy should be more context-dependent ( 7 ).…”

Section: Discussionmentioning

confidence: 99%

Adipocyte‑rich microenvironment promotes chemoresistance via upregulation of peroxisome proliferator‑activated receptor gamma/ABCG2 in epithelial ovarian cancer

Chen,

Liu,

et al. 2024

Int J Mol Med

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The effects of adipocyte-rich microenvironment (ARM) on chemoresistance have garnered increasing interest. Ovarian cancer (OVCA) is a representative adipocyte-rich associated cancer. In the present study, epithelial OVCA (EOC) was used to investigate the influence of ARM on chemoresistance with the aim of identifying novel targets and developing novel strategies to reduce chemoresistance. Bioinformatics analysis was used to explore the effects of ARM-associated mechanisms contributing to chemoresistance and treated EOC cells, primarily OVCAR3 cells, with human adipose tissue extracts (HATES) from the peritumoral adipose tissue of patients were used to mimic ARM in vitro . Specifically, the peroxisome proliferator-activated receptor γ (PPARγ) antagonist GW9662 and the ABC transporter G family member 2 (ABCG2) inhibitor KO143, were used to determine the underlying mechanisms. Next, the effect of HATES on the expression of PPARγ and ABCG2 in OVCAR3 cells treated with cisplatin (DDP) and paclitaxel (PTX) was determined. Additionally, the association between PPARγ, ABCG2 and chemoresistance in EOC specimens was assessed. To evaluate the effect of inhibiting PPARγ, using DDP, a nude mouse model injected with OVCAR3-shPPARγ cells and a C57BL/6 model injected with ID8 cells treated with GW9662 were established. Finally, the factors within ARM that contributed to the mechanism were determined. It was found that HATES promoted chemoresistance by increasing ABCG2 expression via PPARγ. Expression of PPARγ/ABCG2 was related to chemoresistance in EOC clinical specimens. GW9662 or knockdown of PPARγ improved the efficacy of chemotherapy in mice. Finally, angiogenin and oleic acid played key roles in HATES in the upregulation of PPARγ. The present study showed that the introduction of ARM-educated PPARγ attenuated chemoresistance in EOC, highlighting a potentially novel therapeutic adjuvant to chemotherapy and shedding light on a means of improving the efficacy of chemotherapy from the perspective of ARM.

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Section: Discussionmentioning

confidence: 99%

Adipocyte‑rich microenvironment promotes chemoresistance via upregulation of peroxisome proliferator‑activated receptor gamma/ABCG2 in epithelial ovarian cancer

Chen,

Liu,

et al. 2024

Int J Mol Med

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“…In addition to ticagrelor, both clopidogrel and prasugrel have been shown to moderately inhibit BCRP in vitro 49 . Clopidogrel has been shown to increase the AUC of rosuvastatin 2‐fold after administration of a 300 mg loading dose and 1.4‐fold after repeated administration of a 75 mg dose 50 .…”

Section: Discussionmentioning

confidence: 99%

Ticagrelor Increases Exposure to the Breast Cancer Resistance Protein Substrate Rosuvastatin

Lehtisalo,

Tarkiainen,

Neuvonen

et al. 2023

Clin Pharma and Therapeutics

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Ticagrelor and rosuvastatin are often used concomitantly after atherothrombotic events. Several cases of rhabdomyolysis during concomitant ticagrelor and rosuvastatin have been reported, suggesting a drug‐drug interaction. We showed recently that ticagrelor inhibits breast cancer resistance protein (BCRP) and organic anion transporting polypeptide (OATP) 1B1, 1B3, and 2B1 ‐mediated rosuvastatin transport in vitro. The aim of this study was to investigate the effects of ticagrelor on rosuvastatin pharmacokinetics in humans. In a randomized, cross‐over study, nine healthy volunteers ingested a single dose of 90 mg ticagrelor or placebo, followed by a single 10 mg dose of rosuvastatin 1 hour later. Ticagrelor 90 mg or placebo were additionally administered 12, 24, and 36 hours after their first dose. Ticagrelor increased rosuvastatin area under the plasma concentration‐time curve (AUC) and peak plasma concentration 2.6‐fold (90% confidence intervals 1.8‐3.8 and 1.7‐4.0, P=0.001 and P=0.003), and prolonged its half‐life from 3.1 to 6.6 hours (P=0.009). Ticagrelor also decreased the renal clearance of rosuvastatin by 11% (3‐19%, P=0.032). The N‐desmethylrosuvastatin:rosuvastatin AUC0‐10 h ratio remained unaffected by ticagrelor. Ticagrelor had no effect on the plasma concentrations of the endogenous OATP1B substrates glycodeoxycholate 3‐O‐glucuronide, glycochenodeoxycholate 3‐O‐glucuronide, glycodeoxycholate 3‐O‐sulfate, and glycochenodeoxycholate 3‐O‐sulfate, or the sodium‐taurocholate cotransporting polypeptide substrate taurocholic acid. These data indicate that ticagrelor increases rosuvastatin concentrations more than two‐fold in humans, probably mainly by inhibiting intestinal BCRP. Since the risk for rosuvastatin‐induced myotoxicity increases along with rosuvastatin plasma concentrations, using ticagrelor concomitantly with high doses of rosuvastatin should be avoided.

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“…The patients typically receive a large number of concomitant medications in the treatment of cancer, and are prone to cancer medication‐related toxicities and other comorbidities 33,34 . We recently studied 232 commonly used drugs for BCRP inhibition and found 13 new potent BCRP inhibitors 35 . Three of these inhibitors (vemurafenib, bexarotene and everolimus) are antineoplastics while aprepitant is an antiemetic used in the prevention of chemotherapy‐induced vomiting and nausea.…”

Section: Discussionmentioning

confidence: 99%

“…33,34 We recently studied 232 commonly used drugs for BCRP inhibition and found 13 new potent BCRP inhibitors. 35 Three of these inhibitors (vemurafenib, bexarotene and everolimus) are antineoplastics while aprepitant is an antiemetic used in the prevention of chemotherapyinduced vomiting and nausea. In addition, common cardiovascular and non-steroidal anti-inflammatory drugs inhibited BCRP strongly as well.…”

Section: Compoundmentioning

confidence: 99%

Inhibition of efflux transporters by poly ADP‐ribose polymerase inhibitors

Deng

Sistonen

Neuvonen

et al. 2023

Basic Clin Pharma Tox

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Poly ADP‐ribose polymerase (PARP) inhibitors have been approved for the treatment of various cancers. They share similar mechanism of action, but have differences in pharmacokinetic characteristics and potential for drug‐drug interactions (DDI). This study evaluated the potential ATP‐binding cassette transporter‐mediated interactions between PARP inhibitors (niraparib, olaparib, and rucaparib) and statins (atorvastatin and rosuvastatin). We studied the inhibitory activity of PARP inhibitors on breast cancer resistance protein (BCRP), multidrug resistance‐associated protein 3 (MRP3), and P‐glycoprotein (P‐gp) using vesicular transport assays and determined the concentrations required for 50% inhibition (IC50). Then, we predicted the increase of statin exposure followed by the administration of PARP inhibitors using a mechanistic static model. Rucaparib was the strongest inhibitor of BCRP‐mediated rosuvastatin transport (IC50 13.7 μM), followed by niraparib (42.6 μM) and olaparib (216 μM). PARP inhibitors did not affect MRP3. While niraparib appeared to inhibit P‐gp, the inhibition showed large variability. The inhibition of intestinal BCRP by rucaparib, niraparib and olaparib was predicted to elevate rosuvastatin exposure by 52%, 37%, and 24%, respectively. The interactions between PARP inhibitors and rosuvastatin are probably of minor clinical significance alone, but combined with other predisposing factors they may increase the risk of rosuvastatin‐associated adverse effects.

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Novel inhibitors of breast cancer resistance protein (BCRP, ABCG2) among marketed drugs

Cited by 15 publications

References 69 publications

Adipocyte‑rich microenvironment promotes chemoresistance via upregulation of peroxisome proliferator‑activated receptor gamma/ABCG2 in epithelial ovarian cancer

Adipocyte‑rich microenvironment promotes chemoresistance via upregulation of peroxisome proliferator‑activated receptor gamma/ABCG2 in epithelial ovarian cancer

Ticagrelor Increases Exposure to the Breast Cancer Resistance Protein Substrate Rosuvastatin

Inhibition of efflux transporters by poly ADP‐ribose polymerase inhibitors

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