Santacruzamate A, a potent and selective histone deacetylase inhibitor from the Panamanian marine cyanobacterium cf. Symploca sp.

A dark brown tuft-forming cyanobacterium, morphologically resembling the genus Symploca, was collected during an expedition to the Coiba National Park, a UNESCO World Heritage Site on the Pacific coast of Panama. Phylogenetic analysis of its 16S rRNA gene sequence indicated that it is 4.5% divergent from the type strain for Symploca and thus is likely a new genus. Fractionation of the crude extract led to the isolation of a new cytotoxin, designated santacruzamate A (1), which has several structural features in common with suberoylanilide hydroxamic acid [(2), SAHA, trade name Vorinostat], a clinically approved histone deacetylase (HDAC) inhibitor used to treat refractory cutaneous T-cell lymphoma. Recognition of the structural similarly of 1 and SAHA led to the characterization of santacruzamate A as a picomolar level selective inhibitor of HDAC2, a Class I HDAC, with relatively little inhibition of HDAC4 or HDAC6, both Class II HDACs. As a result, chemical syntheses of santacruzamate A as well as a structurally intriguing hybrid molecule, which blends aspects of both agents (1 and 2), were achieved and evaluated for their HDAC activity and specificity.

Patterns of skin metastases: a review of 25 years' experience at a single cancer center.

BACKGROUND: Skin metastases can be defined as the spread of a tumor from its site of primary origin to the skin. Skin metastasis may be the first sign of advanced cancer or an indicator of cancer recurrence. OBJECTIVES: To review patient data of 401 skin metastases available from our institution and compare this information to previously published studies. METHODS: Patient data from the Cancer Registry at RPCI database was reviewed for skin metastasis using vendor software. We included all cases of carcinoma, melanoma, sarcomas, and hematologic malignancies entered during a 25-year period from January 4, 1985, to March 1, 2010. Data identifying the relationship of tumor incidence, morphology, and skin metastasis was reviewed. A total of 401 patients who had skin metastases at the time of cancer diagnosis or had skin metastases as a recurrent site were included in this study. Extensive literature review was conducted using PubMed for articles relating to skin metastases and its clinical presentation and histological features. RESULTS: Breast cancer was the most common cancer to metastasize to the skin (32.7% of all skin metastases seen) followed by bronchus and lung (13.2%), skin (melanoma; 9.5%), lymph nodes (7.5%), oral cavity/pharynx/larynx (6.2%), blood and bone marrow (5.5%), and colorectal (4.2%). The most common histological types of tumors were identified as adenocarcinoma (infiltrating ductal carcinoma [22.7%]), lobular carcinoma (4.7%), and non-adenocarcinoma (squamous cell carcinoma [12.2%] and malignant melanoma [5.2%]). CONCLUSIONS: This is the largest review of skin metastases in the United States in the past 25 years. We found the primary cancers that metastasize to the skin have changed in frequency from previous studies. Our data are helpful in indicating which cancers have the strongest predilection for skin metastasis. Identification of these cancers can help both the clinician and patient detect early signs of metastases, which may allow for earlier diagnosis, implementation of therapy, and possible prolonged survival.

Peroxiredoxin-1 from the human hookworm Ancylostoma ceylanicum forms a stable oxidized decamer and is covalently inhibited by conoidin A.

Hookworms are parasitic nematodes that have a devastating impact on global health, particularly in developing countries. We report a biochemical and structural analysis of a peroxiredoxin from the hookworm Ancylostoma ceylanicum, AcePrx-1. Peroxiredoxins provide antioxidant protection and act as signaling molecules and chaperones. AcePrx-1 is expressed in adult hookworms and can be inactivated by 2,3-bis(bromomethyl)quinoxaline-1,4-dioxide (conoidin A). Conoidin A inactivates AcePrx-1 by alkylating or crosslinking the catalytic cysteines, while maintaining the enzyme in the "locally unfolded" conformation. Irreversible oxidation of the resolving cysteine may contribute additional inhibitory activity. A crystal structure of oxidized AcePrx-1 reveals a disulfide-linked decamer. A helix macrodipole near the active site increases the reactivity of the catalytic cysteines to conoidin A. This work demonstrates the promise of conoidin compounds as probes to evaluate peroxiredoxins as drug targets in human parasites.