Prediction of Broad Spectrum Resistance of Tumors towards Anticancer Drugs

Abstract

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.

Matrine induces the apoptosis of lung cancer cells through downregulation of inhibitor of apoptosis proteins and the Akt signaling pathway

“…In particular, herbs used in Traditional Chinese Medicine (TCM) are gaining wider recognition in recent years as an underexploited source for potential therapeutic compounds (4,5). Matrine ( Fig.…”

Elimination of the chemotherapy resistant subpopulation of 4T1 mouse breast cancer by haploidentical NK cells cures the vast majority of mice

“…The MTT viability assay was performed according to manufacturer's recommendations [19]. 4T1 cells were incubated with increasing concentrations of 4-OH-Cyclophosphamide (the active metabolite of Cyclophosphamide, Niomech-IIT GmbH, Bielefeld, Germany), Cisplatin or Doxorubicin (Pharmachemie BV, Haarlem, the Netherlands).…”

Multi-drug resistance in a canine lymphoid cell line due to increased P-glycoprotein expression, a potential model for drug-resistant canine lymphoma

“…High expression of these ABC-transporters, and P-glycoprotein (P-gp; ABCB1) in particular, has been associated with both a decreased sensitivity to cytotoxic agents, as well as a poor prognosis in several types of cancer in humans (Huang et al, 2004;Gottesman et al, 2002;Kourti et al, 2007;Efferth et al, 2008) and dogs (Bergman et al, 1996;Lee et al, 1996;Steingold et al, 1998;Honscha et al, 2009). Other ABC-transporters associated with DR to cytotoxic agents in humans include multidrug resistance related protein 1 (MRP1; ABCC1) and breast cancer resistance protein (BCRP; ABCG2) (Gillet et al, 2007), both of which have been studied in veterinary medicine (Honscha et al, 2009;Tashbaeva et al, 2007;Schrickx and Fink-Gremmels, 2008;Mealey, 2012), but not in relation to cL.…”

“…Studying the mechanisms responsible for DR will provide a better understanding of DR (Chen and Sikic, 2012) and could potentially lead to the development of new therapies (Efferth et al, 2008;Zhu et al, 2009). For the dog both these goals would be greatly facilitated with a canine in vitro model, but a previously reported DR cell line (Uozurmi et al, 2005) derived from the canine lymphoid GL-1 cell line (Nakaichi et al, 1996) is no longer available.…”

“…Doxorubicin was purposefully chosen given its' efficacy in the treatment of cL, but also because resistance to doxorubicin is predictive for multidrug resistance in human neoplasia (Efferth et al, 2008). The second goal was to assess in both the original and the doxorubicin resistant sub-cell line, the antiproliferative effect of the drugs used in a CHOP-protocol, and the expression and function of the ABC-transporters P-gp, MRP1 and BCRP in both cell lines.…”