Predicting drug sensitivity and resistance

Abstract

For analysis of multidrug resistance, a major barrier to effective cancer chemotherapy, we profiled mRNA expression of the 48 known human ABC transporters in 60 diverse cancer cell lines (the NCI-60) used by the National Cancer Institute to screen for anticancer activity. The use of real-time RT-PCR avoided artifacts commonly encountered with microarray technologies. By correlating the results with the growth inhibitory profiles of 1,429 candidate anticancer drugs tested against the cells, we identified which transporters are more likely than others to confer resistance to which agents. Unexpectedly, we also found and validated compounds whose activity is potentiated, rather than antagonized, by the MDR1 multidrug transporter. Such compounds may serve as leads for development.

Estradiol Induces Export of Sphingosine 1-Phosphate from Breast Cancer Cells via ABCC1 and ABCG2

“…Three ABC transporters, ABCB1 (also known as multidrug resistant gene 1 (MDR1)) or p-glycoprotein, ABCC1 (also known as multidrug resistance protein 1 (MRP1)), and ABCG2 (also known as breast cancer resistance protein), appear to account for 80 -90% of multidrug-resistant human tumor cells (36). In agreement with previous reports (36,37), MCF-7 cells have high expression levels of ABCG2, less ABCC1, and no ABCB1 (Fig. 7A).…”

Melanosomal sequestration of cytotoxic drugs contributes to the intractability of malignant melanomas

“…We have recently identified a cluster of ATP-binding cassette transporters (ABCA9, ABCB5, ABCC2, and ABCD1) that are overexpressed in melanoma cells (14,15). In particular, ABCB5 was found to be preferentially expressed in pigment-producing cells, including melanotic melanoma and the majority of amelanotic melanoma cells (15).…”

Multidrug‐resistant transporter expression does not always result in drug resistance

“…The ABC transporters have been studied extensively for their correlation between CSC and chemoresistance 2, 3. Their ability to efflux xenobiotics, such as chemotherapeutics, makes them interesting targets.…”

“…Stable gene silencing of ABCC1 by shRNAs, however, did not enhance response to gemcitabine (Figure 2C). These contradictory results can be explained by functional redundancy in the ABC family3 and the non‐selectivity of ABC‐targeting agents for specific ABC transporters 5. Together with limitations due to toxicity and adverse drug interactions, this might explain why none of the studies aimed at overcoming drug resistance by ABC members translated into successful clinical application 6…”