Table 1

Examples of antitumor agents that regulate/interfere with the transcriptional machinerya

AgentChemistry/originMechanism of actionbReference
Tamoxifen (antiestrogen)c(Z)-2-[4-(1,2-Diphenyl-1 butenyl)phenoxy]-N,N-dimethylethanamine. Derived from soyInterferes with ER transcriptional activity by competitively inhibiting estradiol binding and inducing conformational changes in the receptor, preventing its interaction with its coactivators 83
GW5638 (antiestrogen)c3-[4-(1,2-Diphenylbut-1-enyl)phenyl]acrylic acidUnique conformational change in the ER. Alternative therapy in tamoxifen-resistant breast tumors 84
ICI 182, 780 (antiestrogen)7 α-alkylamide analogue of estradiolInteraction with ER, through an unidentified allosteric binding site, that results in ER activation and subsequent ER down-regulation 85
W7Naphthalenesulphonamide (calmodulin antagonist)Blocks ER-estrogen response element interaction. Alternative therapy in tamoxifen-resistant breast tumors 86
Analog II (AII)Z-1,1-dichloro-2,3-diphenylcyclopropaneInteraction with type II estrogen-binding sites and subsequent regulation of transcription 87
RetinoidscActivation of retinoic acid response element-mediated transcription and inhibition of AP-1 88
Trichostatin A & leptomycinDerived from Streptomyces sppHDAC inhibitors 89
OxamflatinAromatic sulfonamide hydroxamateHDAC inhibitor 90
MS-275Synthetic benzamineHDAC inhibitor. Selectively induces the expression of TGF-β type II receptor, which is transcriptionally repressed in many human tumors 91
SAHASuberoylanidehydroxamic acidHDAC inhibitor. Activates p21WAF1/Cip1 in a p53-independent manner, through the two Sp1-binding sites located in the promoter of the WAF1 gene 92
FR901228Bicyclic depsipeptide (fungal metabolite)Transcriptional regulation of specific genes via deacetylation of histones 93
Aminothiol WR-1065AminothiolProtects normal tissues from the toxic effects of certain cancer drugs while leaving their antitumor actions unaltered. This effect is mediated through enhanced binding of NF-κB, AP-1, and p53 to their cognate DNA elements 94
ParthenolideSesquiterpene lactone parthenolide from the anti-inflammatory medicinal herb Feverfew (Tanacetum parthenium)Mimicks the function of I-κBα, inhibits I-κB kinase, and blocks STAT3 (signal transducer and activator of transcription 3) activation 95 96 97
DaunomycinAnthracyclineInduction of p53, partially through binding of NF-κB to the NF-κB response element of the p53 promoter 98
PaclitaxelcTaxane derived from the plant Taxus BrevifoliaDegradation of I-κB and subsequent activation of NF-κB 99
AjoeneCompound of garlicActivates NF-κB 100
Sulphur mustardsInhibit the DNA-binding activity of transcription factor AP-2 101
DistamycinsPolyamideInhibit the DNA-binding activity of transcription factors OTF-1 and NF-1 102
Ecteinascidin-743 (ET-743)Marine tetrahydroisoquinoline alkaloid isolated from Ecteinascidia turbinataPromoter-specific blocking agent interfering with the DNA-binding activity of various transcription factors, including E2F, serum response factor, and NF-Y 103 , 104
StaurosporineDerived from Streptomyces staurosporeusInhibits I-κBα and I-κBβ, subsequently leading to activation of NF-κB 105
RituximabcAnti-CD20 monoclonal antibodyDecreases the ability of transcription factor STAT3 to bind to its cognate DNA element 106
PiceatannolPhytochemical stilbene from Euphorbia lagascaeInhibition of transcription factors STAT3 and STAT5 107
Rapamycin & analoges (CCI-779)MacrolideInhibits the protein kinase mammalian target of rapamycin, thus blocking the activity of the ribosomal S6 kinase and the function of the eukaryotic initiation factor 4E-binding protein-1. In addition, it prevents CDK activation and inhibits phosphorylation of RB, thus blocking the activity of E2F-1 108
E7070SulfonamideSuppresses the expression of cyclins A and B1, CDK2, and CDC2 and induces the expression of p21WAF1/Cip1 and p53. In addition, it prevents the phosphorylation of RB, thus blocking activation of E2F-1 109
Mofarotene (RO40-8757)RetinoidDown-regulates, in a tumor-specific manner, the transcription of a mitochondrial gene encoding a subunit of NADH dehydrogenase.b In addition, it up-regulates CDK inhibitors p21WAF11/Cip1 and p27 and shifts RB in its hypophosphorylated form, thus blocking activation of E2F-1 110 ,111
  • a Inhibitors of the BTA, such as actinomycin D and rifamycins, are not included.

  • b In certain cases, the mechanism may be cell or tumor specific. Furthermore, whether the effect on transcription is direct via a GSTF or indirect, remains to be determined.

  • c Used in Phase III clinical trials.