Apolipoprotein A-I (apoA-I) and apoA-I mimetic peptides inhibit tumor development in a mouse model of ovarian cancer

Abstract

We examined whether reduced levels of Apolipoprotein A-I (apoA-I) in ovarian cancer patients are causal in ovarian cancer in a mouse model. Mice expressing a human apoA-I transgene had (i) increased survival (P < 0.0001) and (ii) decreased tumor development (P < 0.01), when compared with littermates, following injection of mouse ovarian epithelial papillary serous adenocarcinoma cells (ID-8 cells). ApoA-I mimetic peptides reduced viability and proliferation of ID8 cells and cis-platinum-resistant human ovarian cancer cells, and decreased ID-8 cell-mediated tumor burden in C57BL/6J mice when administered subcutaneously or orally. Serum levels of lysophosphatidic acid, a well-characterized modulator of tumor cell proliferation, were significantly reduced (>50% compared with control mice, P < 0.05) in mice that received apoA-I mimetic peptides (administered either subcutaneously or orally), suggesting that binding and removal of lysophosphatidic acid is a potential mechanism for the inhibition of tumor development by apoA-I mimetic peptides, which may serve as a previously unexplored class of anticancer agents.

Apolipoprotein A-I: A Molecule of Diverse Function

“…Both apo A-I as well as apo A-I mimetic peptides have the ability to bind pro-inflammatory phospholipids like LPA [41], but the apo A-I mimetic peptides bind LPA with a greater affinity than apo A-I, causing their removal from serum and lowering their serum levels. Thus apo A-I controls the rate of cell proliferation in a tumor and the tumor growth [42].…”

Treatment of patients with cardiovascular disease with L-4F, an apo-A1 mimetic, did not improve select biomarkers of HDL function

“…If much higher doses of peptide will be required in vivo in humans, the cost of producing the peptide may limit the utility of these peptides as clinical therapeutic agents in diseases for which lower-cost treatments are currently effective. A recent publication from our laboratory ( 18 ) demonstrates that the 4F peptide binds lysophosphatidic acid (which induces migration and invasion of both mouse and human epithelial ovarian cancer cells) with extraordinary affi nity (K d = 0.000523 ± 0.0015 nM). It was demonstrated that administering L-4F orally (added to mouse chow at a dose of 100 mg/kg/day) to mice with a normal immune system that had been injected with mouse ovarian epithelial cancer cells signifi cantly reduced both plasma levels of lysophosphatidic acid and tumor burden ( 18 ).…”

“…A recent publication from our laboratory ( 18 ) demonstrates that the 4F peptide binds lysophosphatidic acid (which induces migration and invasion of both mouse and human epithelial ovarian cancer cells) with extraordinary affi nity (K d = 0.000523 ± 0.0015 nM). It was demonstrated that administering L-4F orally (added to mouse chow at a dose of 100 mg/kg/day) to mice with a normal immune system that had been injected with mouse ovarian epithelial cancer cells signifi cantly reduced both plasma levels of lysophosphatidic acid and tumor burden ( 18 ). Assuming that high doses of the 4F peptides will be required, assuming that the cost of production of such peptides will be high, and even assuming that hs-CRP levels would be elevated when the peptide was administered at high doses orally (which seems less likely), the use of these peptides in the treatment of diseases with an unmet clinical need such as ovarian cancer could still be attractive.…”

C1QBP is upregulated in colon cancer and binds to apolipoprotein A-I

“…Zhang et al (25) analyzed the lipid levels of 206 patients with colorectal cancer, 70 patients with benign colorectal disease, and 300 healthy participants, and revealed that serum ApoA-I and ApoB levels were significantly lower in colorectal cancer patients (25). In addition to colon cancer, ApoA-I inhibited tumor development in a mouse model of ovarian cancer (26). Significantly decreased serum levels of ApoA-I were found in patients with cholangiocarcinoma (27), and increased levels in serum were associated with a favorable prognosis in patients with metastatic nasopharyngeal carcinoma (28).…”