Inhibition of breast cancer metastasis to the lungs with UBS109
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Mamoru Shoji1, Wei Ping Qian2, Ganji Purnachandra Nagaraju1, Daniel J. Brat1,3, Danielle Pessolano4, Rick Luzietti4, Spandan Chennamadhavuni5,6, Masayoshi Yamaguchi1, Lily Yang2 and Dennis C. Liotta5,6
1Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA
2Department of Surgery, Emory University, Atlanta, GA 30322, USA
3Department of Pathology, Northwestern University Feinberg School of Medicine and Northwestern Memorial Healthcare, Chicago, IL 60611, USA
4Agilux Laboratories, Inc./Charles River Laboratories, Inc., Worcester, MA 01608, USA
5Emory Institute for Drug Development, Emory University, Atlanta, GA 30322, USA
6Department of Chemistry, Emory University, Atlanta, GA 30322, USA
Mamoru Shoji, email: [email protected]
Keywords: MACs; UBS109; breast cancer; lung metastases; bone metastasis
Received: June 06, 2018 Accepted: September 21, 2018 Published: November 16, 2018
Synthetic monocarbonyl analogs of curcumin (MACs) are cytotoxic against several cancers including head and neck cancer, pancreatic cancer, colon cancer, and breast cancer. Mechanisms of action include depolarization of the mitochondrial membrane potential and inhibition of NF-κB, leading to apoptosis. We previously demonstrated that UBS109 (MAC), has preventive effects on bone loss induced by breast cancer cell lines. We determined whether UBS109 could inhibit and prevent lung metastasis, since lung metastasis of breast cancer is a major problem in addition to bone metastasis. A breast cancer lung metastasis (colonization) model was created by injection of breast cancer cells MDA-MB-231 into the tail vein of athymic nude mice, nu/nu. Animals were treated with vehicle or UBS109 at 5 or 15 mg/kg body weight by intraperitoneal injection once daily 5 days a week for 5 weeks. UBS109 at 15 mg/kg significantly inhibited lung metastasis/colonization as demonstrated by reduced lung weight consisting of tumor nodules. The body weight of animals treated with UBS109 15 mg/kg remained the same as in the other groups. UBS109 killed completely (100%) MDA-MB-231 breast cancer cells at 1.25 μM in a cytotoxicity assay in vitro. UBS109 15 mg/kg i.p. showed a maximal blood concentration (Cmax) of 432 ± 387 ng/mL at 15 min post injection. This is approximately 1.5 ng/ml in the blood of mice and equals 1.5 μM of UBS109. These in vitro and in vivo results are consistent with each other.
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