Microarray-based expression of DNA repair genes does not correlate with growth inhibition of cancer cells by natural products derived from traditional Chinese medicine.
Drug resistance represents a major obstacle in cancer chemotherapy. As chemically characterized compounds derived from plants used in traditional Chinese medicine (TCM) may have molecular targets different from those of standard antitumor drugs, they might be attractive candidates for novel therapeutics with improved pharmacological features. DNA repair is frequently involved in the development of resistance to established anticancer drugs, e.g. alkylating agents. Using a database of 531 chemically characterized TCM compounds from medicinal plants recently established by us, the IC50 values of 60 N.C.I. tumor cell lines for these 531 natural products were tested for correlation with the microarray-based mRNA expression of six genes involved in nucleotide excision repair (ERCC1, XPA, XPC, DDB2, ERCC4, ERCC5). No compound correlated with the expression of these genes, indicating that mRNA expression of these genes is not associated with resistance of the cell lines to these TCM compounds. The same is true for another six genes of the base excision repair pathway (MPG, APEX1, OGG1, XRCC1, LIG3, POLB). Microarray-based COMPARE analyses were performed to identify other candidate genes that are able to predict responsiveness of tumor cells to TCM-derived natural products. As an example, diallyl disulfide from garlic (Allium sativum L., Chinese name: dashuan) was chosen. Eighteen genes were identified whose mRNA expression predicted sensitivity or resistance to diallyl disulfide in hierarchical cluster analyses. Apart from some genes with still unknown function, genes were identified from different functional groups, e.g. signal transducers, regulators of GTPase activity, those associated with cytoskeleton formation and regulation, constituents of the ribosome. Remarkably, none of these genes have been described to be involved in DNA repair. In conclusion, our data indicate that TCM-derived natural products are worth being further investigated as novel compounds to eradicate tumors which reveal resistance to established anti-cancer drugs.
Konkimalla
V S Badireenath
VS
Pharmaceutical Biology (C015), German Cancer Research Center, Heidelberg, Germany.
Wang
Gan
G
Kaina
Bernd
B
Efferth
Thomas
T
D000498:Allyl Compounds / Q000494:pharmacology; D001688:Biological Products / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D016000:Cluster Analysis; D004260:DNA Repair / Q000235:genetics*; D004354:Drug Screening Assays, Antitumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D052138:Genes, Neoplasm; D006801:Humans; D008516:Medicine, Chinese Traditional; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013440:Sulfides / Q000494:pharmacology
D000498:Allyl Compounds; D001688:Biological Products; D012333:RNA, Messenger; D013440:Sulfides; C038491:allyl sulfide