Hyaluromycin, a Novel Hyaluronidase Inhibitor, Attenuates Pancreatic Cancer Cell Migration and Proliferation

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is characterized by accelerated production and degradation of hyaluronan (HA), a major component of extracellular matrix involved in the malignant phenotype of cancer. In particular, increased hyaluronidase (HYAL) activity plays a critical role in cancer progression, at least in part, by producing low-molecular-weight- (LMW-) HA or small fragments of HA, suggesting HYAL as a target for cancer treatment. Hyaluromycin, a new member of the rubromycin family of antibiotics, was isolated from the culture extract of a marine-derived Streptomyces hyaluromycini as a HYAL inhibitor. We investigated the antitumor effects of hyaluromycin in PDAC cells. We examined the effects of hyaluromycin on the proliferation and migration of PDAC cells. To elucidate the mechanisms underlying the effect of hyaluromycin on PDAC cells, we examined the concentration of LMW-HA in the conditioned media after treating PDAC cells with hyaluromycin. We demonstrate that hyaluromycin inhibits proliferation and migration of PDAC cells. We also found that these antitumor effects of hyaluromycin were associated with a decreased concentration of LMW-HA and a decreased phosphorylation of ribosomal protein S6. Our results suggest that hyaluromycin is a promising new drug against this highly aggressive neoplasm.

Hyaluronan activated-metabolism phenotype (HAMP) in pancreatic ductal adenocarcinoma

“…Glycyrrhizin has also been used as a drug delivery carrier for cancer therapy [35]. We also showed that a novel hyaluronidase inhibitor, Hyaluromycin, inhibits proliferation and migration of PDAC cells [36]. These promising agents should be tested for the selective treatment of HAMP+ PDAC in preclinical and clinical studies.…”

The Extracellular Matrix and Pancreatic Cancer: A Complex Relationship

“…Further studies using PEGPH20 have demonstrated that depletion or reduction of hyaluronic acid results in improved tumor perfusion and thus improved delivery of cytotoxic therapy in PDAC mouse models [ 10 , 126 , 127 ]. Moreover, its importance is highlighted by its ability to promote cell survival, proliferation, and invasion via binding to CD44 [ 128 , 129 , 130 , 131 , 132 ] and the receptor for hyaluronic acid-mediated motility (RHAMM) [ 133 ]. In addition to PEGPH20, HA may also be targeted using angiotensin inhibitors, which have been shown to reduce stromal HA and collagen production [ 134 ].…”

Neomenthol prevents the proliferation of skin cancer cells by restraining tubulin polymerization and hyaluronidase activity

“…It was found that neomenthol modulates the enzyme activity up to 10% in EAC cells of mice. A higher expression of hyaluronidase in breast, prostate, bladder, pancreas cancer cells has been reported; however, no report is available on the modulation of hyaluronidase activity in EAC cells, which may either be due to lesser hyaluronidase expression or feeble interaction of hyaluronidase with natural products [61] , [62] , [63] . Therefore, neomenthol did not significantly inhibit the hyaluronidase activity in EAC cells of mice.…”