Bamethan Sulfate

Despite intense research, breast cancer remains the leading cause of cancer-related death in women worldwide, being estrogen receptor-positive (ER⁺) the most common subtype. Nowadays, aromatase inhibitors (AIs), the selective estrogen receptor modulator (SERM) tamoxifen and the selective estrogen receptor down-regulator (SERD) fulvestrant are used as therapeutic options for ER⁺ breast cancer, since they interfere directly with the production of estrogens and with the activation of estrogen-dependent signaling pathways. Despite the success of these treatments, the occurrence of resistance limits their clinical efficacy, demanding the development of novel therapies. Recently, multi-target compounds emerged as promising therapeutic strategies for ER⁺ breast cancer, as they can potentially modulate several important targets simultaneously. In line with this, in this work, the anti-cancer properties and multi-target action of 1,1-Bis(4-hydroxyphenyl)-2-phenylbut-1-ene, tamoxifen bisphenol (1,1-BHPE), were evaluated in an ER⁺ breast cancer cell model (MCF-7aro cells). Molecular docking analysis predicted that 1,1-BHPE was able to bind to aromatase, ERα and ERβ. In vitro studies showed that, although it did not present anti-aromatase activity, 1,1-BHPE reduced aromatase protein levels and interfered with ERα and ERβ signaling pathways, acting as an ERα antagonist and inducing ERβ up-regulation. Through these mechanisms, 1,1-BHPE was able to impair breast cancer growth and induce apoptosis. This represents an important therapeutic advantage because the main players responsible for estrogen production and signaling are modulated by a single compound. To the best of our knowledge, this is the first study describing the anti-cancer properties of 1,1-BHPE as a multi-target compound specific for ER⁺ breast cancer.

Stimulant laxatives are widely used to treat constipation. We investigated in human small and large intestinal preparations the effects of bis‐(p‐hydroxyphenyl)‐pyridyl‐2‐methane (BHPM), the active metabolite of the laxatives bisacodyl and sodium picosulfate on smooth muscle tone and epithelial secretion.

Circular and longitudinal muscle tone of small or large intestinal preparations were recorded with isometric force transducers. Epithelial ion flux (ISC) and tissue resistance was measured with Ussing chamber technique after apical and basolateral BHPM application to large intestinal mucosa/submucosa preparations. Studies were performed in macroscopically normal specimens from 79 patients.

BHPM concentration‐dependently (0.5‐5 μM) increased the tone of circular and longitudinal muscle from small to large intestine. The effect was strongest in large intestinal longitudinal muscle and smallest in small intestinal circular muscle. Increase in muscle tone was prevented by the L‐type Ca++ channel blocker nifedipine but insensitive to the nerve blocker tetrodotoxin. Apical or basolateral BHPM concentration‐dependently decreased or increased ISC, respectively. The KCa1.1 (BK) channel blocker iberiotoxin reversed apical ISC decrease whereas tetrodotoxin reversed basolateral ISC increase. BHPM had no effect on tissue resistance or nerve‐mediated secretory or muscle response with one exception: at the highest concentration basolateral BHPM reduced nerve‐mediated secretion.

BHPM enhanced mucosal secretion and muscle contractility. Results suggested that the laxative effect of BHPM was a consequence of the increase in muscle tone as well as an increased K+ secretion when acting luminally and a nerve‐driven Cl− and HCO3− secretion once acting basolaterally after absorption.