Yi-Fen Wang

Prediction of Broad Spectrum Resistance of Tumors towards Anticancer Drugs

Purpose: Drug resistance is a major obstacle in cancer chemotherapy. Although the statistical probability of therapeutic success is known for larger patient groups from clinical therapy trials, it is difficult to predict the individual response of tumors. The concept of individualized therapy aims to determine in vitro the drug response of tumors beforehand to choose effective treatment options for each individual patient. Experimental Design: We analyzed the cross-resistance profiles of different tumor types (cancers of lung, breast, and colon, and leukemia) towards drugs from different classes (anthracyclines, antibiotics, Vinca alkaloids, epipodophyllotoxins, antimetabolites, and alkylating agents) by nucleotide incorporation and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Hierarchical cluster analysis and COMPARE analyses were applied. Results: Tumors exert broad resistance profiles, e.g., tumors resistant to one drug tend to also be resistant to other drugs, whereas sensitive tumors reveal sensitivity towards many drugs. Interestingly, the broad spectrum resistance phenotype could reliably be predicted by doxorubicin alone. Expression of the ATP-binding cassette transporter P-glycoprotein (ABCB1, MDR1) and the proliferative activity of tumors were identified as underlying mechanisms of broad spectrum resistance. To find novel compounds with activity against drug-resistant tumors, a database with 2,420 natural products was screened for compounds acting independent of P-glycoprotein and the proliferative state of tumor cells. Conclusions: Tumors exert cross-resistance profiles much broader than the classical multidrug resistance phenotype. Broad spectrum resistance can be predicted by doxorubicin due to the multifactorial mode of action of this drug. Novel cytotoxic compounds from natural resources might be valuable tools for strategies to bypass broad spectrum resistance.

Triterpenoid glycoside from Cimicifuga racemosa

One new triterpene glycoside, cimiracemoside (I), and 14 known triterpene glycosides have been isolated from the rhizome extracts of black cohosh (Cimicifuga racemosa). On the basis of spectral and chemical evidence, the structure of the new compound was elucidated to be 12β-acetoxycimigenol-3-O-β-d-xylopranoside (1), and the known compounds were identified to be 25—acetylcimigenol xyloside (2), cimigenol-3-O-β-d-xylopyranoside (3), acetin (4), 27-deoxyacetin (5), cimicifugoside H-1 (6), 23-O-acetylshengmanol 3-O-β-d-xylopranoside (7), foetidinol-3-O-β-xyloside (8), cimicifugoside H-2 (9), 25-O-methylcimigenol xyloside (10), 21-hydroxycimigenol-3-O-β-d-xylopyranoside (11), 24-epi-7,8—didehydrocimigenol-3-xyloside (12), cimidahurinine (13), cimidahurine (14) and cimifugin (15). The compounds 1–5, 14, and 15 showed weak antibacterial activities in the agar diffusion assay.

Diterpenoid Alkaloids from Aconitum brachypodum

Three new C-19 diterpene alkaloids, along with two known ones, were isolated from the roots of Aconitum brachypodum Diels. The structures of the new alkaloids were established as N-deethyl-3-Oacetylchasmaconitine (1), N-deethyl-3-O-acetylyunaconitine (2), and N-deethyl-3-O-acetyljesaconitine (3). Their structures were elucidated by extensive spectroscopic methods, including 1D (1H, 13C) NMR and 2D NMR (1H–1H COSY, TOCSY, ROESY, HSQC, and HMBC) experiments, as well as high-resolution electrospray ionization mass spectrometry (HR-ESI-MS).