Tetracyclines: a pleitropic family of compounds with promising therapeutic properties. Review of the literature

Abstract

There must be something unique about a class of drugs (discovered and developed in the mid-1940s) where there are more than 130 ongoing clinical trials currently listed. Tetracyclines were developed as a result of the screening of soil samples for antibiotic organisms. The first of these compounds chlortetracycline was introduced in 1948. Soon after their development tetracyclines were found to be highly effective against various pathogens including rickettsiae, Gram-positive, and Gram-negative bacteria, thus, becoming a class of broad-spectrum antibiotics. The mechanism of action of tetracyclines is thought to be related to the inhibition of protein synthesis by binding to the 30S bacterial ribosome. Tetracyclines are also an effective anti-malarial drug. Over time, many other "protective" actions have been described for tetracyclines. Minocycline, which can readily cross cell membranes, is known to be a potent anti-apoptotic agent. Its mechanism of action appears to relate to specific effects exerted on apoptosis signaling pathways. Another tetracycline, doxycycline is known to exert antiprotease activities. Doxycycline can inhibit matrix metalloproteinases, which contribute to tissue destruction activities in diseases such as gingivitis. A large body of literature has provided additional evidence for the "beneficial" actions of tetracyclines, including their ability to act as oxygen radical scavengers and anti-inflammatory agents. This increasing volume of published work and ongoing clinical trials supports the notion that a more systematic examination of their possible therapeutic uses is warranted. This review provides a summary of tetracycline's multiple mechanisms of action and while using the effects on the heart as an example, this review also notes their potential to benefit patients suffering from various pathologies such as cancer, Rosacea, and Parkinson's disease.

Effects of a timely therapy with doxycycline on the left ventricular remodeling according to the pre-procedural TIMI flow grade in patients with ST-elevation acute myocardial infarction

“…The best characterized non-antimicrobial property of the doxycycline is its ability to inhibit members of the MMP family of endopeptidases [12], many of which are largely up-regulated in the setting of animal [19][20][21] and human [22,23] hearts after MI. Previous studies have also shown that doxycycline has some ability to inhibit reactive oxygen species (ROS) [24].…”

“…Several pleiotropic properties of doxycycline related mainly to its ability to act as metalloproteinases (MMPs) inhibitor can explain these beneficial effects [12].…”

Farmacocinética y efectos adversos de la doxiciclina en el tratamiento de la Ehrlichiosis: fundamentos teóricos para ensayos clínicos en caninos

“…Algunos estudios han descrito, que a altas dosis el uso de doxiciclina puede bajar la tasa de filtración glomerular causando estados de isquemia en la arteriola eferente que puede llegar a inducir el incremento en los valores de creatinina sérica, una de las teorías es la reducción en el estrés oxidativo, disminuyendo los niveles de citoquinas e inhibición de la actividad de metaloproteinasas de matriz (5,30). Se ha determinado en diferentes estudios las propiedades antiinflamatorias e inmunomoduladoras de la doxiciclina asociadas a estos efectos (31,32).…”

“…One of the theories is the reduction of the oxidative stress, decreasing cytokine levels and inhibiting the activity of matrix metalloproteinases (5,30). The anti-inflammatory and immunomodulatory properties of doxycycline associated with these effects have been determined in different studies (31,32). …”

Cellular and molecular effect of antitumor agents

“…Por lo tanto, las tetraciclinas, además de inhibir estas metaloproteasas, también impiden su producción, ya que interfieren en la activación proteolítica de pro-MMP, mediante la quelación de zinc en la zona de unión con la enzima, bloqueando la actividad de MMPs. Particularmente, se ha demostrado que la doxiciclina (figura 1) es más efectiva que la minociclina en la inhibición de MMPs (García-Álvarez & Oteo, 2010;Griffin, Fricovsky, Ceballos & Villarreal, 2010).…”