L12- ABCG

what does BCRP stand for

breast cancer-related protein

what is BCRP

new resistance transporter first identified in a breast cancer cell line

where is BCRP expressed

4q22.1

• other tissues and relevant to drug excretion

what is another word for BCRP

MXR

• mitoxantrone-resistance protein

describe the structure of ABCG2/BCRP

• single spanning transporter

• smaller than ABCB and ABCC families- only one set of membrane spanning domains (MSD)

• Half-transporter

• Form homodimers

what is the weight of ABCG2/BCRP

~70KDa

give an example of ABCG2/BCRP forming a homodimer

BCRP

give examples of ABCG2/BCRP forming heterodimers

• ABCG5

• ABCG8

describe the location of ABCG2/BCRP

• high levels in lactating breast

• secretion of xenobiotic into milk which has implications for breast-fed infants

• restrictions on use of certain drugs by nursing mothers

what do some studies say Imatinib is a substrate for

ABCG2/BCRP

CML stem cells appear to have higher levels of ABCG2/BCRP than…

more mature CML cells

why do CML stem cells appear to have higher levels of ABCG2/BCRP than more mature CML cells

less sensitive to imatinib and likely to remain after mature cells are eliminated

what does some evidence suggest that imatinib resistance involves decreased levels of regulatory miRNA (miR-212), resulting in…

increased ABCG2/BCRP levels in leukemic cells

describe Imatinib-mediated inhibition of BCR-ABL

downregulation of ABCG2/BCRP levels posttranscriptionally via the PI3K-Akt pathway

what are RTKs

enzyme coupled receptors with mediated growth factor signalling

what is TKI targeted treatment of

targeting specific signaling pathways deregulated in cancers

TKIs are non-toxic and more specific compared with…

traditional cytotoxic chemotherapies, but have problems with acquired resistance

what is a relative substrate of ABCG2/BCRP transporter anthracyclines

daunorubicin

what is a relative substrate of ABCG2/BCRP transporter Epipodophyllotoxins

etoposide

what are relative substrates of ABCG2/BCRP transporter kinase inhibitors

• dasatinib

• erlotinib

• gefitinib

• imatinib

• lapatinib

• nilotinib

• sorafenib

• sunitinib

• vandetanib

what is a relative substrate of ABCG2/BCRP transporter campthotecins

Irinotecan (CPT-11)

(ABCG2/BCRP) GWAS showed that genetic polymorphism which results in an amino acid change in BCRP is a risk factor for…

gout

describe gout

accumulation of uric acid as crystals in joints occurs resulting in pain and inflammation

what is uric acid a substrate for

ABCG2/BCRP

what does an unstable form of uric acid being a substrate for ABCG2/BCRP result in

poor ability to excrete this compound

what is uric acid generated by

purine metabolism

how does accumulation of uric acid in the body cause effects in the joints and kidney

• high levels in synovial fluid

• uric acid kidney stones

what does Q141K gout cause

mutation changes in NBD structure

how can the unstable protein in Q141K gout be compensated for

second mutation H155A

what are strategies to overcome ABC mediated MDR

• chemical inhibitors

• natural compounds

• antibodies

• reduced expression (siRNA,miRNA)

• agents that bypass transporters

• novel delivery systems (nanotechnology)

what were inhibitors of MDR1 developed to overcome

MDR in cancer

give examples of first generation MDR1 inhibitors

• verapamil

• quinidine

• amiodarone

• cyclosporine A

give examples of second generation MDR1 inhibitors

• valspodar

• dexverapamil

give examples of third generation MDR1 inhibitors

• dofequidar

• zosuquidar

• tariquidar

• elacridar

• biricodar

verapamil sensitises…

MDR cells to chemotherapy

further studies show 5681014 and BSO sensitise MPR1-expressing cells to chemotherapy such as…

vincristine and doxorubicin

• but NOT cisplatin

list the difficulties of targeting ABC transporters

• physiological roles of ABC transporters

• ubiquitous expression

• transporter redundancy

• dose adjustment and monitoring when combining inhibitors with drugs with a narrow therapeutic window