Abstract
A growing body of literature supports the role of apolipoproteins present in HDL in the treatment of pro-inflammatory diseases including cancer. We examined whether bovine HDL (bHDL) and three dual-domain peptides, namely AEM-28 and its analog AEM-28–2, and HM-10/10, affect tumor growth and development in mouse models of ovarian and colon cancer. We demonstrate that bHDL inhibits mouse colorectal cancer cell line CT26-mediated lung tumor development, and mouse ovarian cancer cell line ID8-mediated tumor burden. We also demonstrate that, although to different degrees, dual-domain peptides inhibit cell viability of mouse and human ovarian and colon cancer cell lines, but not that of normal human colonic epithelial cells or NIH3T3 mouse fibroblasts. Dual-domain peptides administered subcutaneously or in a chow diet decrease CT26 cell-mediated tumor burden, tumor growth, and tumor dissemination in BALB/c mice. Plasma levels of lysophosphatidic acid (LPA) are significantly reduced in mice that received bHDL and the dual-domain peptides, suggesting that reduction by effecting accumulation and/or synthesis of pro-inflammatory lipids may be one of the mechanisms for the inhibition of tumor development by bHDL and the dual-domain peptides. Our studies suggest that therapeutics based on apolipoproteins present in HDL may be novel agents for the treatment of epithelial adenocarcinomas of the ovary and colon.
Highlights
When considering the cohort of patients with gynecologic malignancy, the deadliest of these cancers are the high-grade epithelial adenocarcinoma of Mullerian cell origin and collectively represents the 5th most frequent cause of cancer-related deaths in women overall
We examined whether bovine High-density lipoprotein (HDL) and three dual-domain peptides, namely AEM28 and its analog apoE mimetic peptide -28 (AEM-28)-2, and HM-10/10, affect tumor growth and development in mouse models of ovarian and colon cancer
Cell viability was approximately 30% lower in CT26 cells treated with bovine HDL (bHDL) (100μg/mL) when compared to no treatment controls (Figure 1A)
Summary
When considering the cohort of patients with gynecologic malignancy, the deadliest of these cancers are the high-grade epithelial adenocarcinoma of Mullerian cell origin (e.g. ovarian, fallopian tube, primary peritoneal papillary serous adenocarcinoma) and collectively represents the 5th most frequent cause of cancer-related deaths in women overall. In spite of its extremely low incidence (an annual incidence of 11.6 cases/100,000 women per year) [1], the WHO reports a significant global impact, approximately 225,500 new cases of epithelial ovarian cancer (EOC) will be diagnosed worldwide annually, with approximately 140,200 (62%) of these patients, succumbing to their disease [1]. Colon cancer (CC), is one of the most devastating diseases and represents the second deadliest cancer (second only to lung cancer), and the third most common cancer diagnosed, in the United States [2]. The development of novel forms of targeted therapy is necessary to positively impact patient survival and reduce the morbidity and mortality burden associated with these devastating cancers [7,8,9,10]
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