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Thalidomide attenuates nitric oxide‐driven angiogenesis by interacting with soluble guanylyl cyclase
Author(s) -
Majumder Syamantak,
Rajaram Megha,
Muley Ajit,
Reddy Himabindu S,
Tamilarasan KP,
Kolluru Gopi Krishna,
Sinha Swaraj,
Siamwala Jamila H,
Gupta Ravi,
Ilavarasan R,
Venkataraman S,
Sivakumar KC,
Anishetty Sharmila,
Kumar Pradeep G,
Chatterjee Suvro
Publication year - 2009
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2009.00446.x
Subject(s) - angiogenesis , soluble guanylyl cyclase , thalidomide , sodium nitroprusside , nitric oxide , pharmacology , in vivo , endothelial stem cell , chemistry , sildenafil , angiogenin , biochemistry , cancer research , medicine , biology , in vitro , immunology , guanylate cyclase , microbiology and biotechnology , organic chemistry , multiple myeloma
Background and purpose: Nitric oxide (NO) promotes angiogenesis by activating endothelial cells. Thalidomide arrests angiogenesis by interacting with the NO pathway, but its putative targets are not known. Here, we have attempted to identify these targets. Experimental approach: Cell‐based angiogenesis assays (wound healing of monolayers and tube formation in ECV304, EAhy926 and bovine arterial endothelial cells), along with ex vivo and in vivo angiogenesis assays, were used to explore interactions between thalidomide and NO. We also carried out in silico homology modelling and docking studies to elucidate possible molecular interactions of thalidomide and soluble guanylyl cyclase (sGC). Key results: Thalidomide inhibited pro‐angiogenic functions in endothelial cell cultures, whereas 8‐bromo‐cGMP, sildenafil (a phosphodiesterase inhibitor) or a NO donor [sodium nitroprusside (SNP)] increased these functions. The inhibitory effects of thalidomide were reversed by adding 8‐bromo‐cGMP or sildenafil, but not by SNP. Immunoassays showed a concentration‐dependent decrease of cGMP in endothelial cells with thalidomide, without affecting the expression level of sGC protein. These results suggested that thalidomide inhibited the activity of sGC. Molecular modelling and docking experiments revealed that thalidomide could interact with the catalytic domain of sGC, which would explain the inhibitory effects of thalidomide on NO‐dependent angiogenesis. Conclusion and implications: Our results showed that thalidomide interacted with sGC, suppressing cGMP levels in endothelial cells, thus exerting its anti‐angiogenic effects. These results could lead to the formulation of thalidomide‐based drugs to curb angiogenesis by targeting sGC.