A Small Peptide Targeting the Ligand-Induced Androgen Receptor/Filamin a Interaction Inhibits the Invasive Phenotype of Prostate Cancer Cells

Prostate cancer (PC) is one of the most widespread malignancies among males worldwide. The androgen receptor (AR) plays a major role in prostate cancer development and progression and is the main target of PC therapy. Nonetheless, its action is not yet fully elucidated. We report here that the AR associates with Filamin A (FlnA) promoting migration and invasiveness of various PC-derived cells after androgen challenging. Inhibition of the AR/FlnA complex assembly by a very low concentration of Rh-2025u, an AR-derived peptide specifically interfering with this association, impairs such phenotype in monolayer cells and in 3D models. This study, together with our recent data in cancer-associated fibroblasts (CAFs), indicates that targeting the AR/FlnA complex could improve the clinical management of invasive PC, as the limited number of new drugs reaching the market suggests that we must re-examine the way invasive PC is currently treated. In this context, the synthesis of new biologically active molecules, such as the Rh-2025u peptide, which has been shown to efficiently interfere in the complex assembly in CAFs and PC cells, should overcome the limits of current available therapies, mostly based on hormone antagonists.

Conservative Management of Uterine Adenomyosis: Medical vs. Surgical Approach

Uterine adenomyosis is a commonly encountered estrogen-dependent disease in reproductive-age women, causing heavy menstrual bleeding, intense pelvic pain, and infertility. Although adenomyosis was previously considered a disease of multiparous women, it is becoming increasingly evident that it also affects younger nulliparous women and may compromise their fertility potential. It is clear that hysterectomy, the standard approach to definitively manage the disease, is not an option for patients wishing to preserve their fertility, so there is an urgent need to develop novel conservative strategies. We searched the current literature for available methods for conservative management of adenomyosis, including both pharmacological and surgical approaches. There is no existing drug that can cure adenomyosis at present, but some off-label treatment options may be used to tackle disease symptoms and improve fertility outcomes. Adenomyosis in patients wishing to conceive can be ‘treated’ by conservative surgery, though these procedures require highly experienced surgeons and pose a considerable risk of uterine rupture during subsequent pregnancies. While currently available options for conservative management of adenomyosis do have some capacity for alleviating symptoms and enhancing patient fertility perspectives, more effective new options are needed, with gonadotropin-releasing hormone antagonists showing encouraging results in preliminary studies.

Coumarins and Gastrointestinal Cancer: A New Therapeutic Option?

Cancers of the gastrointestinal (GI) tract are often life-threatening malignancies, which can be a severe burden to the health care system. Globally, the mortality rate from gastrointestinal tumors has been increasing due to the lack of adequate diagnostic, prognostic, and therapeutic measures to combat these tumors. Coumarin is a natural product with remarkable antitumor activity, and it is widely found in various natural plant sources. Researchers have explored coumarin and its related derivatives to investigate their antitumor activity, and the potential molecular mechanisms involved. These mechanisms include hormone antagonists, alkylating agents, inhibitors of angiogenesis, inhibitors of topoisomerase, inducers of apoptosis, agents with antimitotic activity, telomerase inhibitors, inhibitors of human carbonic anhydrase, as well as other potential mechanisms. Consequently, drug design and discovery scientists and medicinal chemists have collaborated to identify new coumarin-related agents in order to produce more effective antitumor drugs against GI cancers. Herein, we summarize the therapeutic effects of coumarin and its derivatives against GI cancer.

Mistaken administration of a repeat loading dose of Degarelix leading to acute psychosis

Lesson Advanced and metastatic prostate cancer is often managed with hormonal blockage. Luteinising hormone-releasing hormone antagonists achieve rapid testosterone suppression and are used for the treatment of advanced or metastatic prostate cancer. Degarelix is a luteinising hormone-releasing hormone antagonist and is given as a loading dose, followed by a monthly maintenance dose. We report a case where a patient was inadvertently given a second loading dose of Degarelix that resulted in acute psychosis in the form of panic attacks, delusions, suicidal thoughts, insomnia and some visual hallucinations, which are not reported as side-effects of Degarelix.

Stress-induced alterations of social behavior are reversible by antagonism of steroid hormones in C57/BL6 mice

Various disturbances of social behavior, such as autism, depression, or posttraumatic stress disorder, have been associated with an altered steroid hormone homeostasis and a dysregulation of the hypothalamus–pituitary–adrenal axis. A link between steroid hormone antagonists and the treatment of stress-related conditions has been suggested. We evaluated the effects of stress induction on social behavior in the three chambers and its potential reversibility upon specific steroid hormone antagonism in mice. C57BL/6 mice were stressed twice daily for 8 days by chronic swim testing. Social behavior was evaluated by measuring, first, the preference for sociability and, second, the preference for social novelty in the three-chamber approach before and after the chronic swim test. The reversibility of behavior upon stress induction was analyzed after applying steroid hormone antagonists targeting glucocorticoids with etomidate, mineralocorticoids with potassium canrenoate, and androgens with cyproterone acetate and metformin. In the chronic swim test, increased floating time from 0.8 ± 0.2 min up to 4.8 ± 0.25 min was detected (p < 0.01). In the three-chamber approach, increased preference for sociability and decreased preference for social novelty was detected pre- versus post-stress induction. These alterations of social behavior were barely affected by etomidate and potassium canrenoate, whereas the two androgen antagonists metformin and cyproterone acetate restored social behavior even beyond baseline conditions. The alteration of social behavior was better reversed by the androgen as compared with the glucocorticoid and mineralocorticoid antagonists. This suggests that social behavior is primarily controlled by androgen rather than by glucocorticoid or mineralocorticoid action. The stress-induced changes in preference for sociability are incompletely explained by steroid hormone action alone. As the best response was related to metformin, an effect via glucose levels might confound the results and should be subject to future research.

Degarelix as a neoadjuvant hormonal therapy for acute urinary tract toxicity associated with external beam radiotherapy for intermediate- and high-risk prostate cancer: a propensity score matched analysis

Background In prostate cancer treatment, lower urinary tract symptoms significantly improve with luteinizing hormone-releasing hormone antagonists use compared with agonists. However, it is unclear whether luteinizing hormone-releasing hormone antagonists can decrease acute urinary tract toxicity during external beam radiotherapy. This study aimed to assess whether luteinizing hormone-releasing hormone antagonists used as neoadjuvant therapy reduced acute urinary tract toxicity during external beam radiotherapy compared with luteinizing hormone-releasing hormone agonists. Methods The study included 78 patients who underwent intensity-modulated radiation therapy for intermediate- and high-risk prostate cancer between April 2013 and January 2020. Irradiation was initiated after 3–6 months of neoadjuvant therapy. Androgen deprivation therapy was given to the intermediate-risk group for 6 months and the high-risk group for 2–3 years. The European Organization for Research and Treatment of Cancer/Radiation Therapy Oncology Group toxicity grading scale was used to evaluate the urinary tract system toxicity. Relevant clinical factors were used in matching patients based on propensity scores to enable comparison between the groups. Results Each group had 27 matched patients. There was no reduction in urinary tract toxicity with the use of luteinizing hormone-releasing hormon antagonists (P = 0.624). For patients with an International Prostate Symptom Score of ≥11 at the start of treatment, 18 patients in each group were matched. Significantly lower scores were observed in the luteinizing hormone-releasing hormon antagonist group (P = 0.041). Conclusions Luteinizing hormone-releasing hormon antagonists may reduce acute urinary tract toxicity during prostate cancer external beam radiotherapy compared with luteinizing hormone-releasing hormon agonists, in particular in patients with moderate to severe symptoms at the start of treatment.