The potential of Atorvastatin for chronic lung diseases therapy.

Atorvastatin (ATO) is of the statin class and is used as an orally administered lipid-lowering drug. ATO is a reversible synthetic competitive inhibitor of 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase thus leading to a reduction in cholesterol synthesis. It has recently been demonstrated that ATO has different pharmacological actions, which are unrelated to its lipid-lowering effects and has the ability to treat chronic airway diseases. This paper reviews the potential of ATO as an anti-inflammatory, antioxidant, and anti-proliferative agent after oral or inhaled administration. This paper discusses the advantages and disadvantages of using ATO under conditions associated with those found in the airways. This treatment could potentially be used to support the formulating of ATO as an inhaler for the treatment of chronic respiratory diseases.

The role of hypertrophic chondrocytes in regulation of the cartilage-to-bone transition in fracture healing.

Endochondral bone formation is an important pathway in fracture healing, involving the formation of a cartilaginous soft callus and the process of cartilage-to-bone transition. Failure or delay in the cartilage-to-bone transition causes an impaired bony union such as nonunion or delayed union. During the healing process, multiple types of cells including chondrocytes, osteoprogenitors, osteoblasts, and endothelial cells coexist in the callus, and inevitably crosstalk with each other. Hypertrophic chondrocytes located between soft cartilaginous callus and bony hard callus mediate the crosstalk regulating cell-matrix degradation, vascularization, osteoclast recruitment, and osteoblast differentiation in autocrine and paracrine manners. Furthermore, hypertrophic chondrocytes can become osteoprogenitors and osteoblasts, and directly contribute to woven bone formation. In this review, we focus on the roles of hypertrophic chondrocytes in fracture healing and dissect the intermingled crosstalk in fracture callus during the cartilage-to-bone transition.

Protein kinase C ß inhibition by enzastaurin leads to mitotic missegregation and preferential cytotoxicity toward colorectal cancer cells with chromosomal instability (CIN).

Enzastaurin is a selective inhibitor of protein kinase C ß and a potent inhibitor of tumor angiogenesis. In addition, enzastaurin shows direct cytotoxic activity toward a subset of tumor cells including colorectal cancer cells (CRC). In spite of promising results in animal models, the clinical activity of enzastaurin in CRC patients has been disappointing although a subset of patients seems to derive benefit. In the present study we investigated the biological and cytotoxic activities of enzastaurin toward a panel of well-characterized CRC cell lines in order to clarify the mechanistic basis for the cytotoxic activity. Our results show that enzastaurin is significantly more cytotoxic toward CRC cells with chromosome instability (CIN) compared to cells with microsatellite instability (MSI). Since CIN is usually attributed to mitotic dysfunction, the influence of enzastaurin on cell cycle progression and mitotic transit was characterized for representative CIN and MSI cell lines. Enzastaurin exposure was accompanied by prolonged metaphase arrest in CIN cells followed by the appearance of tetraploid and micronuclei-containing cells as well as by increased apoptosis, whereas no detectable mitotic dysfunctions were observed in MSI cells exposed to isotoxic doses of enzastaurin. Our study identifies enzastaurin as a new, context dependent member of a heterogeneous group of anticancer compounds that induce "mitotic catastrophe," that is mitotic dysfunction accompanied by cell death. These data provide novel insight into the mechanism of action of enzastaurin and may allow the identification of biomarkers useful to identify CRC patients particularly likely, or not, to benefit from treatment with enzastaurin.