Advances in mechanisms of resistance to aromatase inhibitors.

Clinically, there are two distinct types of aromatase inhibitor (AI) resistance, namely acquired and innate resistance. Because the underlying mechanisms of these two types of resistance may not be mutually exclusive, strategies to tackle these resistances may not be effective when used interchangeably. Activation of growth factor receptor pathways is the hallmark of acquired AI resistance. These pathways can be targeted either at the cell surface receptor level or their downstream signaling cascades. Currently, everolimus in combination with exemestane represents a new standard of care for patients progressing on non-steroidal AIs. HDAC inhibitors have also shown promising results For innate resistance, the combination of fulvestrant and AI in the front line setting represents a new treatment option, particularly for patients who present with de novo metastatic disease. A Phase III trial is currently ongoing to evaluate the benefit of CDK 4/6 inhibitor, palbociclib, in the first line setting in combination with AI.

[Progress in study of the structure, catalytic mechanism and inhibitors of aromatase].

Aromatase is a key enzyme responsible for in vivo estrogen biosynthesis. Inhibition of the activity of the aromatase has become an alterative way for treatment of breast cancer. In this review, the structure and catalytic mechanism of the aromatase is briefly introduced followed by thorough review of the progress in the study of the steroidal and non-steroidal aromatase inhibitors. This review is focused on the natural compounds that exhibit the aromatase inhibition, which include flavonoids, xanthones, coumarins, and sesquiterpenes. The structure-activity relationship of these compounds is also discussed.

[Bone and Men's Health. Effects of aromatase inhibitors on human osteoblasts].

Aromatase inhibitors (AIs) have been widely employed as an adjuvant endocrine therapy in postmenopausal patients with estrogen receptor (ER) positive breast carcinoma in place of tamoxifen. AIs work on suppressing both systemic and local estrogen biosynthesis in an almost complete manner resulting in estrogen depletion and subsequently inhibition of estrogen dependent carcinoma cell proliferation. Despite marked therapeutic effects in these patients, potential side effects related to long term and marked estrogen depletion should be considered for the benefits of these patients. Among these possible side effects, bone loss and/or increased rates of pathological fractures may be considered one of the most serious complications in terms of effecting activities of daily life of the patients. AIs can be classified into two types, steroidal and non-steroidal in terms of their structure and modes of actions. The former is also characterized to display androgenic actions. Estrogens are well-known to exert their effects primarily through osteoblasts in human bone tissues. Therefore, in this review, we will summarize in vitro effects of AIs, especially androgenic effects of steroidal AIs upon human osteoblasts in order to further understand their effects on human skeletal systems.

Mechanism-based categorization of aromatase inhibitors: a potential discovery and screening tool.

Cytochrome P450 aromatase is a key steroidogenic enzyme that converts androgens to estrogens in vertebrates. There is much interest in aromatase inhibitors (AIs) both because of their use as pharmaceuticals in the treatment of estrogen-sensitive breast cancers, and because a number of environmental contaminants can act as AIs, thereby disrupting endocrine function in humans and wildlife through suppression of circulating estrogen levels. The goal of the current work was to develop a mechanism-based structure-activity relationship (SAR) categorization framework highlighting the most important chemical structural features responsible for inhibition of aromatase activity. Two main interaction mechanisms were discerned: steroidal and non-steroidal. The steroid scaffold is most prominent when the structure of the target chemical is similar to the natural substrates of aromatase - androstenedione and testosterone. Chemicals acting by non-steroidal mechanism(s) possess a heteroatom (N, O, S) able to coordinate the heme iron of the cytochrome P450, and thus interfere with steroid hydroxylation. The specific structural boundaries controlling AI for both analyzed mechanisms were defined, and a software tool was developed that allowed a decision tree (profile) to be built discriminating AIs by mechanism and potency. An input chemical follows a profiling path and the structure is examined at each step to decide whether it conforms with the structural boundaries implemented in the decision tree node. Such a system would aid drug discovery efforts, as well as provide a screening tool to detect environmental contaminants that could act as AIs.

Comparative assessment of the inhibition of recombinant human CYP19 (aromatase) by azoles used in agriculture and as drugs for humans.

Azoles (imidazoles and triazoles) are used as antifungal agents in agriculture and in medicine, and also for antiestrogen therapy, e.g., for breast cancer treatment. Antifungal activity is based on inhibition of fungal CYP51 (lanosterol 14alpha-demethylase), and estrogen biosynthesis reduction is due to azole inhibition of CYP19 (aromatase). Inhibition of aromatase by antifungal agents is usually an unwanted side effect and may cause endocrine disruption. A fluorimetric assay based on human recombinant CYP19 enzyme with dibenzylfluorescein as a substrate was used to compare the inhibitory potency of 22 azole compounds. Dose responses were established and duplicate datasets were analyzed with a nonlinear mixed-effects model with cumulative normal distribution for the logarithm of concentration. IC50 values (50% inhibitory concentration) of 13 fungicides used in agriculture ranged more than 700-fold, starting from 0.047 microM. The potency of seven human drugs spanned more than 7000-fold, starting from 0.019 microM. Most potent fungicides included prochloraz, flusilazole, and imazalil, and most potent medicinal antifungals were bifonazole, miconazole, and clotrimazole. These in vitro data indicate that the top-ranking azoles used as antifungal agents or drugs are as potent inhibitors of aromatase as are antiestrogen therapeutics used to treat breast cancer. These putative effects of azole agents and drugs on steroid biosynthesis and sex hormone balance should be considered when used in human subjects and also in wildlife exposed to azole fungicides used in agriculture.