Aurora kinase inhibitors: a new class of drugs targeting the regulatory mitotic system

The present review gives a perspective on the Aurora kinase family members, their function in normal cells, their role in cancer progression as well as their potential as target for anticancer treatment. Mitosis has been an important target for anticancer therapy development, leading to some specific drugs mainly addressing Tubulines, as a key structure of the mitotic spindle. Vinca alkaloids, taxanes or epotilones are good examples of conventionally developed antimitotic agents. However, novel classes of antineoplastic drugs are being studied, targeting the regulatory system that controls functional aspects of mitosis, such as Aurora or Polo-like kinases or Kinespondin inhibitors. The specific role of the different Aurora kinase proteins as regulator enzymes of the mitotic process in normal cells is discussed. Some of the mechanisms that link Aurora overexpression with cancer are also considered. Thereafter, the clinical and preclinical development of the different Aurora kinase inhibitors is presented. This is nowadays a very active area of therapeutic research and at least, sixteen new compounds are being studied as potential antineoplastic drugs. Most of them are in a very early phase of clinical development. However, we summarized the most recently published findings related with these drugs: main characteristics, way of administration, dose limiting toxicities and recommended doses for further studies. Another important aspect in Aurora kinase inhibition is the study and validation of potential biomarkers to optimize the clinical development. Several studies included pharmacodynamic assessments in normal blood cells, skin or/and tumor biopsies. Several proposals included a higher mitotic index, a decreased number of mitosis with bipolar spindles or normal alignment of chromosomes and inhibition of histone H3 phosphorylation. Future strategies and challenges for trials with Aurora kinase inhibitors are also discussed (AU)

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A review of the effectiveness of antimitotic drug injections for hypertrophic scars and keloids.

Hypertrophic scars and keloids are common problems after injury and cause functional and cosmetic deformities. A wide variety of treatments have been advocated for hypertrophic scars and keloids regression. Unfortunately, the reported efficacy has been variable. This article explores antimitotic drugs described in the literature such as steroid injection, 5-FU, mitomycin C, and bleomycin, which mainly target the fibroblasts in scar tissue, have been proposed as the effective modalities for scar treatment and scar prevention after surgery, but restricted due to possible side effects. The current accepted treatment for hypertrophic scar and keloid are combination therapy and the early treatment which could achieve better efficacy and less adverse effect.

Aurora kinase inhibitors: a new class of drugs targeting the regulatory mitotic system.

The present review gives a perspective on the Aurora kinase family members, their function in normal cells, their role in cancer progression as well as their potential as target for anticancer treatment. Mitosis has been an important target for anticancer therapy development, leading to some specific drugs mainly addressing Tubulines, as a key structure of the mitotic spindle. Vinca alkaloids, taxanes or epotilones are good examples of conventionally developed antimitotic agents. However, novel classes of antineoplastic drugs are being studied, targeting the regulatory system that controls functional aspects of mitosis, such as Aurora or Polo-like kinases or Kinespondin inhibitors. The specific role of the different Aurora kinase proteins as regulator enzymes of the mitotic process in normal cells is discussed. Some of the mechanisms that link Aurora overexpression with cancer are also considered. Thereafter, the clinical and preclinical development of the different Aurora kinase inhibitors is presented. This is nowadays a very active area of therapeutic research and at least, sixteen new compounds are being studied as potential antineoplastic drugs. Most of them are in a very early phase of clinical development. However, we summarized the most recently published findings related with these drugs: main characteristics, way of administration, dose limiting toxicities and recommended doses for further studies. Another important aspect in Aurora kinase inhibition is the study and validation of potential biomarkers to optimize the clinical development. Several studies included pharmacodynamic assessments in normal blood cells, skin or/and tumor biopsies. Several proposals included a higher mitotic index, a decreased number of mitosis with bipolar spindles or normal alignment of chromosomes and inhibition of histone H3 phosphorylation. Future strategies and challenges for trials with Aurora kinase inhibitors are also discussed.

The complex role of AR signaling after cytotoxic insult: implications for cell-cycle-based chemotherapeutics.

Prostatic adenocarcinomas are dependent on androgen receptor (AR) signaling for growth and progression, in part through the ability of AR to induce G1-S phase cell cycle transition. Hormonal therapies that inhibit AR activity are the first line of intervention for disseminated disease, and are initially quite effective; however, recurrent, incurable tumors ultimately arise with restored AR function. Given the importance of AR in governing the potentiation of this tumor type, there has been a dedicated interest in dissecting the mechanisms by which AR promotes prostate cancer proliferation and survival. Recent studies have challenged the utility of manipulating AR activity to enhance cell death in combination with genotoxic insult. Herein, the role of AR in controlling cell cycle progression and paradoxical roles of AR in survival signals are considered, as are the potential implications of these findings for chemotherapeutic response. Although there is much to be resolved, the present data suggest that knowledge of AR action in promoting cellular proliferation can be utilized for the design of coordinate strategies that maximize cell death in response to cytotoxic chemotherapeutics.