Hyaluronic-acid butyric esters as promising antineoplastic agents in human lung carcinoma: A preclinical study

Abstract

New promising compounds, derived from the esterification of hyaluronic acid with butyric acid, were investigated in vitro on a non-small cell lung carcinoma cell line (NCI-H460) and an its metastatic subclone (NCI-H460M). All new compounds exerted a dose-dependent inhibitory effect on both cell lines, which expressed CD44, the specific surface receptor for hyaluronic acid, in a very high percentage of cells (90%). HE1, the most effective of these compounds, was 10-fold more effective than sodium butyrate (NaB) in inhibiting cell proliferation. Similarly to NaB, after 24 hours of treatment, HE1 affected the expression of three cell cycle-related proteins (p27(kip1), p53 and p21(waf1)) responsible for growth arrest, indicating that the presence of the hyaluronic acid backbone does not interfere with the biologic activity. Intratumoral treatment with HE1 demonstrated a marked efficacy on primary tumor growth and on lung metastases formation of the murine Lewis Lung Carcinoma model. Altogether, present findings suggest a possible clinical application of these novel butyric pro-drugs in primary and metastatic lung cancer.

Inhibition of Hepatocellular Carcinomas in vitro and Hepatic Metastases in vivo in Mice by the Histone Deacetylase Inhibitor HA-But

“…In conclusion, the present results indicate that HA-But, a compound in which HA is esterified with butyric ester and which has been previously reported to block lung cancer growth and spread (11), could be useful also for the selective treatment of intrahepatic lesions. Undoubtedly, the use of HDACi as anticancer agents is not new and some of these agents (phenylbutyrate, suberoylanilide hydroxamic acid, MS-275, and depsipeptide) are currently included in Phase I/II clinical trials for the treatment of solid tumors, lymphomas, and multiple myeloma (Refs.…”

“…HA-But, characterized by a 0.06 degree of substitution (the ratio between the number of substituted hydroxyl groups and the number of the repeating disaccharide units of polysaccharide), was prepared as described elsewhere (11). Briefly, the esterification reaction was accomplished by means of an activated reactive form of But, i.e., an adduct between butyric anhydride and 4-dimethylaminopyridine.…”

“…Because a major challenge in cancer therapy is to selectively target cytotoxic agents to tumor cells and at the same time reduce the side effects of these agents, we developed HA-But, a new chemical entity constituted by a backbone of hyaluronic acid (HA) partially esterified with butyric acid (But), the smallest HDACi (11). One of the main characteristics of HA-But is its strong affinity for CD44 (12), the specific membrane receptor for HA, which is overexpressed in most human cancers, including liver carcinoma (13).…”

Anticancer Therapeutics: Targeting Macromolecules and Nanocarriers to Hyaluronan or CD44, a Hyaluronan Receptor

“…57 Intratumoral treatment of non-small cell lung carcinoma bearing mice showed a decrease in the number of metastatic colonies in the lung. 64 However, intravenous injection resulted in rapid accumulation in clearance organs. 57 HA-drug conjugates have effective cytotoxicity at a cellular level, but studies performed in vivo often did not employ intravenous dosing, opting for intratumoral, subcutaneous or intraperitoneal injection, and avoided many HA clearance mechanisms.…”

Hyaluronan Endocytosis: Mechanisms of Uptake and Biological Functions

“…Although there are relatively few in vivo studies that have evaluated the efficacy of HA bioconjugates, previous investigations with a paclitaxol-HA bioconjugate have shown that it inhibits tumor growth of RT-112/84 human transitional cell carcinomas in mice and increases the survival of mice that had been inoculated with the NMP-1 or SK-OV-3ip human ovarian carcinoma lines [66,67]. Similarly, a butyrate-HA bioconjugate was found to inhibit tumor growth and reduced lung metastasis in mice inoculated with LL3 murine lung carcinoma cells [68]. Thus, a number of reports reinforce the concept that HA may be useful as a drug carrier / ligand targeting delivery agent.…”