Cancer chemotherapy with indole-3-carbinol, bis(3'-indolyl)methane and synthetic analogs.
Indole-3-carbinol (I3C) conjugates are phytochemicals expressed in brassica vegetables and have been associated with the anticancer activities of vegetable consumption. I3C and its metabolite bis(3'-indolyl)methane (DIM) induce overlapping and unique responses in multiple cancer cell lines and tumors, and these include growth inhibition, apoptosis and antiangiogenic activities. The mechanisms of these responses are complex and dependent on cell context. I3C and/or DIM activate or inactivate multiple nuclear receptors, induce endoplasmic reticulum stress, decrease mitochondrial membrane potential, and modulate multiple signaling pathways including kinases. DIM has been used as a template to synthesize a series of 1,1-bis(3'indolyl)-1-(substituted aromatic)methanes (i.e. C-DIMs) which are also cytotoxic to cancer cells and tumors. Some of the effects of C-DIMs resemble those reported for DIM analogs; however, structure-activity studies with the aromatic ring has resulted in generation of highly unique receptor agonists. For example, p-trifluoromethylphenyl, p-t-butylphenyl and p-biphenyl analogs activate peroxisome proliferator-activated receptor gamma (PPARgamma), and p-methoxyphenyl and p-phenyl compounds activate nerve growth factor-induced-Balpha (NGFI-Balpha, Nur77) orphan nuclear receptor. The effects of C-DIMs on PPARgamma and Nur77 coupled with their receptor-independent activities has resulted in the development of a novel group of multi-targeted anticancer drugs with excellent potential for clinical treatment of cancer.
Safe
Stephen
S
Department of Veterinary Physiology and Pharmacology, Texas A&M University, 4466 TAMU, Vet. Res. Building 410, College Station, TX 77843-4466, USA. ssafe@cvm.tamu.edu
Papineni
Sabitha
S
Chintharlapalli
Sudhakar
S
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000502:physiology; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D047495:PPAR gamma / Q000187:drug effects / Q000502:physiology; D011944:Receptors, Androgen / Q000032:analysis; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects / Q000502:physiology; D011960:Receptors, Estrogen / Q000187:drug effects / Q000502:physiology; D011987:Receptors, Steroid / Q000502:physiology; D013329:Structure-Activity Relationship
C505816:1,1-bis(3'-indolyl)-1-(4-t-butylphenyl)methane; D016588:Anticarcinogenic Agents; D004268:DNA-Binding Proteins; D007211:Indoles; C539821:NR4A1 protein, human; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D047495:PPAR gamma; D011944:Receptors, Androgen; D018336:Receptors, Aryl Hydrocarbon; D011960:Receptors, Estrogen; D011987:Receptors, Steroid; C016517:indole-3-carbinol