Novel camptothecin analogues that circumvent ABCG2‐associated drug resistance in human tumor cells

Abstract

Key words: SN-38; CPT analogue; ABCG2; SAR; DNA topoisomerase I inhibitorCamptothecin (CPT) is an antitumor alkaloid that was originally isolated from Camptotheca acuminata, a tree native to southern China. 1 CPT has been demonstrated to inhibit mammalian DNA topoisomerase I (Topo I), the nuclear enzyme that changes the topologic state of duplex DNA by single-strand breakage and resealing. Stabilization of the covalent Topo I-DNA complex (so-called cleavable complex) by CPT is a critical step in its antitumor action where Topo I-mediated DNA breaks are induced via prevention of DNA relegation. 2 Clinical and preclinical studies, however, revealed reversible bone marrow depression and hemorrhagic cystitis as the major dose-limiting toxicities of CPT. Thus, efforts have been directed at finding new CPT analogues with higher antitumor activity and less toxicity.Irinotecan (7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin; CPT-11) has been synthesized and developed as a new water-soluble analogue of CPT with wide-spectrum antitumor activity against many types of human tumor cells. 3,4 CPT-11 is a prodrug, the antitumor activity of which is exerted by 7-ethyl-10-hydroxycamptothecin (SN-38), the active metabolite of CPT-11. 5 Despite enormous expense and efforts spent on the development of cancer chemotherapies, acquired and intrinsic drug resistance in tumors is the major obstacle to long-term sustained patient response to chemotherapy. Hitherto several mechanisms for the resistance to SN-38 and its analogues have been proposed, e.g., mutations or decreased expression of Topo I, increased expression of the UGT1A protein or single nucleotide polymorphisms (SNPs) of the UGT1A gene, increased activity of O 6 -methylguanine-DNA-methyltransferase, a DNA repair protein, decreased activity of carboxylesterase that catalyzes the biosynthesis of SN-38 from CPT-11 in the plasma and liver and overexpression of drug export pumps. 6 -11 It has been documented that several ATP-binding cassette (ABC) transporters, such as P-glycoprotein (ABCB1/MDR1/P-gp) and multidrug resistance-associated protein 1 (ABCC1/MRP1), can cause drug resistance in tumor cells by actively extruding antitumor drugs. 12,13 Recently, a novel ABC transporter, ABCG2, also known as breast cancer-resistant protein (BCRP/MXR1/ ABCP), has been discovered in drug-resistant cell lines selected for by mitoxantrone or Topo I inhibitors. 14,15 Overexpression of ABCG2 has been shown to confer resistance to doxorubicin, mitoxantrone and various CPT analogues. 14,16,17 In a recent study with plasma membrane vesicles prepared from ABCG2-overexpressing SN-38-selected human small cell lung carcinoma cells, we found that ABCG2 transported SN-38 and its glucuronide metabolite in an ATP-dependent manner. 18 Thus, it is highly likely that ABCG2 actively extrudes SN-38 from tumor cells and thereby confers drug resistance.To circumvent ABCG2-associated drug resistance, in the present study we have synthesized a total of 14 different analogues of CPT and examine...

Structural Determinants of Imidazoacridinones Facilitating Antitumor Activity Are Crucial for Substrate Recognition by ABCG2

“…Moreover, we found that the presence of a corresponding R1 position hydroxyl is necessary to facilitate ABCG2-mediated drug resistance also toward the distinct pharmacological group of TAs. In accord, a recent study on the nature of ABCG2 interaction with camptothecin analogs has revealed a similar dependence on the presence of hydroxyl or amine groups on the outer ring of their common camptothecin structure, possibly facilitating hydrogen bond formation, essential for substrate recognition and efflux via ABCG2; these camptothecin positions seem to be analogous to the present R1, R2, or R3 positions of IAs (Yoshikawa et al, 2004). Several subsequent publications on ABCG2-dependent resistance to novel camptothecin analogs have also obeyed this general hydrogen bond rule (Rajendra et al, 2003;Bates et al, 2004;Takagi et al, 2007).…”

Role of the Breast Cancer Resistance Protein (BCRP/ABCG2) in Drug Transport—an Update

“…Although the number of known BCRP substrates is now over 200, not much work has been done to analyze structure-activity relationship (SAR). The only SAR study was for camptothecin analogs, and the authors found that BCRP preferentially transports the camptothecin analogs with high polarity at carbon positions 10 and 11 over those with low polarity (41). We have recently developed a predictive model for BCRP substrates using a support vector machine (SVM) method based on 263 known BCRP substrates and non-substrates (42).…”

Structure–Activity Relationships and Quantitative Structure–Activity Relationships for Breast Cancer Resistance Protein (ABCG2)

“…The high-performance liquid chromatography retention time of the compounds, as measured using a reverse phase column, correlated inversely with the drug resistance ratio where compounds with a short retention time had higher ratios and vice versa. The SAR showed that SN-355, SN-392, and SN-398 have similar substituents on the 10 and 11 positions making these compounds susceptible to transport by ABCG2 like SN-38 (37). Based on the SAR, it was speculated that the remaining SN-38 analogues would be able to circumvent efflux by ABCG2.…”