Role of Reactivating Mutant p53 Protein in Suppressing Growth and Metastasis of Triple-Negative Breast Cancer.

Tumor suppressor p53 protein (p53) plays a vital role throughout the body to conserve DNA stability and prevent cancer. Normally, wild-type p53 protein (wtp53) is either degraded or bound to a negative regulator and is inactive. When damage to DNA occurs within a cell, p53 protein is induced and causes cell cycle arrest. This gives cells a chance to repair, but if damage is too severe, cells undergo apoptosis and are rejected. Mutations in the p53 gene (mtp53) are associated with a variety of cancers and occur in 70-80% of cases of triple-negative breast cancer (TNBC). Importantly, many mutations occur in the DNA binding domain of p53 gene and the altered mutant p53 protein (mtp53) is subsequently not degraded. High levels of mtp53 protein accumulate within the cell, leading to the development of tumors. Therefore, converting mtp53 protein back into its functional wild-type conformation is a promising means by which to prevent or reverse tumor development. Herein we will briefly examine how tumor suppressor wtp53 exerts its effects, the mechanisms involved in protecting cells that undergo DNA damage and ways in which wtp53 prevents tumorigenesis. Using TNBC as an example, we will describe the use of specific compounds to reactivate mtp53 protein function by reconfiguring its structure and outline the potential benefits of mtp53 protein reactivation. We will also briefly discuss current clinical trials aimed at reactivating mtp53 protein in order to cure certain cancers. Finally, we make the recommendation that greater emphasis should be placed on testing naturally occurring compounds that are generally non-toxic to re-activate mtp53 protein and control progression of TNBC.

Doxycycline and tissue repair in rats.

Iterations in collagen turnover are integral to tissue repair. Repair gone awry, as a result of excess collagen accumulation or degradation, can contribute to pathologic ventricular remodeling. Pharmacologic interventions that would attenuate either aspect of faulty repair have therefore attracted interest. Tetracyclines, which inhibit both collagen synthesis and degradation, as well as angiogenesis, may hold promise, unrelated to their antimicrobial properties, in this regard. Assessment of their potential in rodent hearts with experimental injury can be problematic, given the often microscopic nature of tissue repair and brief involvement of matrix metalloproteinases (MMPs). We therefore selected a subcutaneous model in which granulation and fibrous tissues form over several weeks in response to croton oil and where fibrous tissue is subsequently resorbed because of high levels of collagenolytic activity. Untreated rats were compared with those given daily oral doxycycline (40 mg/kg). We harvested pouch tissue and exudate weekly for 5 weeks to assess hydroxyproline concentration and MMP activity (gelatin substrate zymography) of pouch wall and mononuclear cell count of pouch exudate. At week 2, neovascularization in pouch wall was measured by means of intravenous infusion of carmine-red dye in gelatin. The resultant "vascular cast" was solubilized and dye content quantitated with the use of spectrophotometry. Serum was assayed weekly for type I collagen carboxyterminal telopeptide (ICTP), a marker of collagen degradation. During weeks 1 and 2 and compared with untreated controls, doxycycline-treated rats had attenuated pouch tissue weight, collagen concentration, MMP2 lytic activity and vascularity, and reduced exudate volume and mononuclear cells. In vitro, doxycycline inhibited tissue gelatinolytic activity in a dose-dependent manner. At weeks 4 and 5, pouches were larger and collagen concentration was higher in doxycycline-treated rats, and serum ICTP levels were reduced at weeks 3 and 4. During the initial phase of pouch development, doxycycline exerts an inhibitory effect on tissue formation, likely mediated through its attenuation of angiogenesis and modulations of collagen turnover. As repair proceeds in subsequent weeks, doxycycline retards collagen degradation and pouch resorption by inhibiting MMPs. Doxycycline offers a multifaceted pharmacologic profile with which to modify various aspects of tissue repair in the rat.

Glucocorticoids and laminitis in the horse.

The administration of exogenously administered GCs and syndromes associated with GC excess are both attended by increased risk for the development of laminitis in adult horses. However, there exists substantial controversy as to whether excess GCs cause laminitis de novo. If true, the pathogenesis of laminitis arising from the effects of GC excess is probably different from that associated with diseases of the gastrointestinal tract and endotoxemia. Although a satisfactory explanation for the development of laminitis as a consequence of GC action is currently lacking, numerous possible and plausible theoretical mechanisms do exist. Veterinarians must exert caution with respect to the use of GCs in adult horses. The extent to which individual horses are predisposed to laminitis as a result of GC effect cannot be predicted based on current information. However, the administration of systemic GCs to horses that have been previously affected by laminitis should be used only with extreme caution, and should be accompanied by careful monitoring for further signs of laminitis. The risk of laminitis appears to be greater during treatment using some GCs (especially dexamethasone and triamcinalone) compared with others (prednisone and prednisolone). Whenever possible, to reduce the risk of laminitis, GCs should be administered locally. For example, the risk of GC-associated laminitis is evidently considerably reduced in horses affected with chronic obstructive pulmonary disease (COPD) if GC treatment is administered via inhalation. We have hypothesized that structural changes in the equine hoof that resemble laminitis may arise as a consequence of excess GC effect. Although these changes are not painful per se, and are not associated with inflammation, they could likely predispose affected horses to the development of bona fide laminitis for other reasons. Moreover, the gross morphological appearance of the chronically GC-affected hoof resembles that of a chronically foundered hoof in some respects. Further investigation into the effect of GC on the hoof lamellar interface is clearly needed.