Determination of the glucuronide metabolite of ON 013100, a benzylstyrylsulfone antineoplastic drug, in colon cancer cells using LC/MS/MS

Abstract

ON 013100, (E)-2,4,6-trimethoxystyryl-3-hydroxy-4-methoxybenzyl sulfone, is a potent kinase inhibitor whose phosphate form is in Phase I clinical trials in lymphoma and acute lymphoid leukemia. The objectives were to: (a) investigate the possible presence of the glucuronide metabolite of the drug in two representative colon cancer cell lines, a drug resistant (colo-205) and a drug sensitive (colo-320); (b) quantify the glucuronide metabolite and the unchanged drug in the cells after treatment with ON 013100. The glucuronide was synthesized and a selective LC/MS/MS method was developed and validated for the characterization and quantification of the metabolite. The glucuronide metabolite (570.6 Da) was found in the drug-resistant cells upon a 1 h incubation with ON 013100 (20 μg/ml). After treatment with the drug, the concentration of the metabolite gradually decreased from 0.84 μg/ml at 0 h through 0.21 μg/ml at 6 h to below detection limit of 8.0 ng/ml at 9 h. No glucuronide metabolite was detected in the drug-sensitive cells. The concentrations of intact ON 013100 in the drug-resistant cells gradually decreased from 0.41 μg/ml (0 h) to 0.06 μg/ml (9 h). The corresponding concentrations of the intact drug in the drug-sensitive cells were from 2.88 μg/ml to 0.94 μg/ml.

<p>Metabolite Profiling in Anticancer Drug Development: A Systematic Review</p>

“…Out of 78 articles included in the analysis (42 in vitro, 42 in vivo, and 16 clinical studies), 47 (60.3%), 14 (17.9%) and 17 (21.8%) articles respectively, investigated metabolite profiles of conventional anticancer drugs/synthetic anticancer candidates, small-molecules targeted therapy, and herbderived compounds with anticancer activities. These studies involved a total of 57 (57.0%) conventional anticancer drugs/ synthetic anticancer candidates, 6, 22 (22.0%) studies for small-molecules targeted therapy, 4,5,[59][60][61][62][63][64][65][66][67][68][69][70] and 21 (21.0%) studies for herb-derived compounds with anticancer activities 2,3,7,9,[71][72][73][74][75][76][77][78][79][80][81][82][83] (Tables 1-3). Anticancer drugs or candidate compounds are metabolized by either Phase I, or phase II metabolizing enzyme alone, or both phase I and phase II metabolizing enzymes.…”

“…Antitumor (breast carcinoma), Apoptotic induction SN30000 (3-(3-Morpholinopropyl)-7,8-dihydro-6H-indeno[5,6-e] [1,2,4] triazine 1.4-dioxide: tirapazamine analog)[6,94] Antiproliferative (Human colon cancer (HT29) and cervical (SiHa) cancer cells), Antitumor (HT29 and SiHa cancer cells models)Tamoxifen[54,55] Antiestrogen(Breast cancer) TAS-102 (tipiracil hydrochloride (TPI) + trifluridine (FTD)) [56] Anticancer (Metastatic colorectal cancer) TNP-470 (O-(chloroacetyl-carbamoyl) fumagillol) [57] Antitumor (B16 BL6 melanoma, M 5076 reticulum cell sarcoma, Lewis lung carcinoma, Walker 256 carcinoma), Anticancer, Antiangiogenesis TW01003 ((3E,6E)-3-Benzylidene-6-[(5-hydroxypyridin-2-yl) methylene] piperazine-2,5-dione) induction, and Migration reduction (Leukemia, cervical, breast cancer, and laryngeal carcinoma) Brivanib [60,95] Anticancer (Hepatocellular carcinoma) EPZ-5676 (pinometostat) [61] Anticancer (Leukemia) HM781-36B (1-[4-[4-(3,4-dichloro-2-fluorophenylamino)-7methoxyquinazolin-6-yloxy]-piperidin-1-yl] prop-2-en-1-one hydrochloride) [5] Anticancer (Advanced solid tumors i.e. non-small-cell lung cancer (NSCLC) patients with EGFR mutation (T790M), breast, , non-small-cell lung, and gastric cancer and glioblastoma cells models) Lenvatinib [66] Anticancer (Hepatocellular carcinoma, melanoma, renal carcinoma, non-small-cell lung carcinoma, glioblastoma multiforme, ovarian and endometrial carcinoma)Neratinib[67] Anticancer (Breast cancer) ON 013100 ((E)-2,4,6-trimethoxystyryl-3-hydroxy-4methoxybenzyl sulfone (Kinase inhibitor))[68] Anticancer (Lymphoma and acute lymphoid leukemia) Osimertinib[69] Anticancer (Non-small cell lung cancer) Pimasertib[70] Anticancer (Non-small cell lung, colorectal cancer, and head and neck squamous cell carcinoma) TKI258 (dovitinib)[96] Anticancer (Renal cell carcinoma, advanced breast cancer, relapsed multiple myeloma and urothelial cancer)…”