Inhibition of breast cancer metastasis to the lungs with UBS109

Abstract

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 (C_max) 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.

Keywords: MACs; UBS109; bone metastasis; breast cancer; lung metastases.

Figure 1. Chemical structures of the monocarbonyl analogs of synthetic curcumin (MACs), EF24, EF31, and UBS109

Molecular weights of curcumin, EF24, EF31, and UBS109 are 368.38, 311.11, 277.12, and 291.35 g/mol, respectively. Cytotoxic activity and solubility of the MACs are described [11].

Figure 2. The luciferase activity in breast cancer cells

The luciferase activity of breast cancer cells and their distribution after injection of cells into the tail vein of mice. Mice were treated with intraperitoneal injection of vehicle (A) or UBS109 at 5 or 15 mg/kg/body weight (B) or (C) once daily for 5 days per a week (from Monday through Friday) for approximately 5 weeks (n = 4/treatment regimen).

Figure 3. Hematoxylin and eosin stains of the breast tumors in the lungs

Hematoxylin and eosin stains of the breast tumors in the lungs from the vehicle- or UBS109 (15 mg/kg, i.p.)-treated mice. Arrows indicate the tumors. Number indicates the total magnification of the image through the microscope.

Figure 4. Body weight (gram) of the mice

Body weight (gram) of the mice during treatment with UBS109 (at 5 or 15 mg/kg body weight, i.p.) or vehicle.

Figure 5. Pharmacokinetic study of UBS109

Mean UBS109 plasma concentration (ng/mL) at 0.5, 2 and 8 hours after a single i.p. injection of UBS109 at 15 mg/kg body weight. This pharmacokinetic study was performed by the Agilux Lboratories, Worcester, MS 01608, USA (incorporated now with the Charles River Laboratories).