SR16388: a steroidal antiangiogenic agent with potent inhibitory effect on tumor growth in vivo

Abstract

Angiogenesis is one of the major processes controlling growth and metastasis of tumors. Angiogenesis inhibitors have been targeted for the treatment of various cancers for more than 2 decades. We have developed a novel class of steroidal compounds aimed at blocking the angiogenic process in cancerous tissues. Our lead compound, SR16388, is a potent antiangiogenic agent with binding affinity to estrogen receptor-α (ER-α) and -β (ER-β) at the nanomolar range. This compound inhibited the proliferation of human microvascular endothelial cells (HMVEC) and various types of human cancer cells in vitro. SR16388 inhibited embryonic angiogenesis as measured in the chick chorioallantoic membrane (CAM) assay. The blood vessel density in the CAM was greatly reduced after the embryos were treated with 3 μg/CAM of SR16388 for 24 h. SR16388 at a dose of 2 μM prevented tube formation in Matrigel after HMVEC cells were treated for 8 h. In a modified Boyden chamber assay, SR16388 inhibited the migration of HMVECs by 80% at 500 nM. Using a novel in vivo Fibrin Z-chamber model, we demonstrated that SR16388 at a single daily oral dose of 3 mg/kg for 12 days significantly inhibited the granulation tissue (GT) thickness and the microvessel density of the GT as compared to control. More importantly, SR16388 down-regulated the pro-angiogenic transcription factors, hypoxia inducible factor 1α (HIF-1α) and signal transducer and activator of transcription 3 (STAT3) in non-small cell lung cancer (NSCLC) cells. Together, these effects of SR16388 can lead to the reduction of vascularization and tumor growth in vivo.

Estrogen-Related Receptors in Breast Cancer and Prostate Cancer

“…On the other hand, diethylstilbestrol (DB00255) and the tamoxifen metabolite, 4-hydroxytamoxifen, have been shown to interact with ERRβ and ERRγ and act as antagonists ( 82 , 83 ). SR16388, a novel steroidal antiestrogen, inhibits the interaction between its coactivator peroxisome proliferator-activated receptor γ coactivator-1 α to inhibit ERR α activity ( 84 ).…”

Current and Future Development of Estrogen Receptor Ligands: Applications in Estrogen-Related Cancers

“…Moreover, HIF-1 activates the transcription of many genes that encode for proteins that are involved in angiogenesis, glucose metabolism, cell proliferation/survival and invasion/metastasis, and HIF-1 constitutive activation is linked to increased tumor growth and increased mortality [136]. The notion that in prostate cancer cells ER can induce in a ligand-dependent fashion the destabilization of HIF-1 via proteasomal degradation support the role of ER as the main mediator of SR16388 biological effects [138,139]. SR16388 is currently in late-stage preclinical development, which will prepare the agent for entry into human clinical trials.…”

Novel drugs that target the estrogen-related receptor alpha: their therapeutic potential in breast cancer

“…126,127 This novel steroidal compound was developed by SRI International for the treatment of breast, prostate, ovarian, and colon cancer in the hope that it would inhibit the effects of estrogen-related receptor alpha on energy metabolism of tumor cells by inhibition of hypoxia-inducible factor 1-alpha and hence prevent tumor cell survival in hypoxic conditions by prevention of angiogenesis and induction of apoptosis 126,127. SR16388 also inhibits estrogen receptor alpha.…”

“…SR16388 also inhibits estrogen receptor alpha. Malignant cell growth in xenograft models is inhibited with an IC 50 of around 0.2 μM and the inhibition is potentiated in the presence of microtubulin inhibitors such as paclitaxel or vincristine 127. Promulgated for treatment of tamoxifen-resistant breast cancer and bicalutamide-resistant prostate cancer, SR16388 has completed Phase I trials, as well as Phase II trials for different tumor types.…”