Anticancer drugs may have proarrhythmic effects including drug-induced QT interval prolongation, which is of particular importance because it can lead to a fatal polymorphic ventricular tachycardia termed torsade de pointes (TdP). QT interval prolongation and TdP are rare life-threatening untoward effects of anticancer therapy, particularly with arsenic trioxides and anthracyclines, and even some novel molecular targeted drugs touted as ‘tumor specific’. Several factors that affect myocardial repolarization can further increase the risk of TdP. This article reviews the mechanism of QT interval prolongation, risk factors for TdP and the QT toxicity of anticancer drugs as well as its management. Specific attention should be paid to high-risk populations such as patients with underlying heart diseases, electrolyte imbalance and bradycardia. To minimize the occurrence of QT interval prolongation and TdP, it is advisable to conduct a careful risk factor assessment before antitumor therapy. To this end, several new biomarkers have been introduced to predict TdP triggering and recent studies have pointed out the potential clinical relevance of genetic testing.

The interleukin (IL)‐6/glycoprotein (GP)130/signal transducer and activator of transcription (STAT)3 pathway is emerging as a target for the treatment of hepatocellular carcinoma. IL‐6 binds to IL‐6R, forming a binary complex, which further combines with GP130 to transduce extracellular signaling by activating STAT3. Therefore, blocking the interaction between IL‐6 and GP130 may inhibit the IL‐6/GP130/STAT3 signaling pathway and its biological effects. It has been reported that bazedoxifene acetate (BAZ), a selective estrogen receptor modulator approved by the US Food and Drug Administration, could inhibit IL‐6/GP130 protein‐protein interactions. Western blot, immunofluorescence staining, wound healing and colony formation assays were used to detect the effect of BAZ on liver cancer cells. Cell viability was evaluated by MTT assay. Apoptosis of cells was determined using the Annexin V‐FITC detection kit. Mouse xenograft tumor models were utilized to evaluate the effect of BAZ in vivo. Our data showed that BAZ inhibited STAT3 phosphorylation (P‐STAT3) and expression of STAT3 downstream genes, inducing apoptosis in liver cancer cells. BAZ inhibited P‐STAT3 induced by IL‐6, but not by leukemia inhibitory factor. BAZ inhibited P‐STAT1 and P‐STAT6 less significantly as elicited by interferon‐α, interferon‐γ and IL‐4. In addition, pretreatment of BAZ impeded the translocation of STAT3 to nuclei induced by IL‐6. BAZ inhibited cell viability, wound healing and colony formation in vitro. Furthermore, tumor growth in HEPG2 mouse xenografts were significantly inhibited by daily intragastric gavage of BAZ. Our results suggest that BAZ inhibited the growth of hepatocellular carcinoma in vitro and in vivo, indicating another potential strategy for HCC prevention and therapy.

The role of IL-6 signalling in hypertensive heart disease and its sequelae is controversial. Our group demonstrated that Bazedoxifene suppressed IL-6/gp130 signalling in cancer cells but its effect on myocardial pathology induced by pressure overload is still unknown. We explored whether Bazedoxifene could confer benefits in wildtype C57BL/6J mice suffering from transverse aortic constriction (TAC) and the potential mechanisms in H9c2 myoblasts. Mice were randomized into three groups (Sham, TAC, TAC+Bazedoxifene, n = 10). Morphological and histological observations suggested TAC aggravated myocardial remodelling while long-term intake of Bazedoxifene (5 mg/kg, intragastric) attenuated pressure overload-induced pathology. Echocardiographic results indicated Bazedoxifene rescued cardiac function in part. We found Bazedoxifene decreased the mRNA expression of IL-6, MMP2, Col1A1, Col3A1 and periostin in murine hearts after 8-week surgery. By Western blot detection, we found Bazedoxifene exhibited an inhibition of STAT3 activation in mice three hours and 8 weeks after TAC. Acute TAC stress (3 hours) led to downregulated ratio of LC3-Ⅱ/LC3-Ⅰ, while in mice after long-term (8 weeks) TAC this ratio becomes higher than that in Sham mice. Bazedoxifene inverted the autophagic alteration induced by TAC at both two time-points. In H9c2 myoblasts, Bazedoxifene suppressed the IL-6-induced STAT3 activation. Moreover, IL-6 reduced the ratio of LC3-Ⅱ/LC3-Ⅰ, promoted P62 expression but Bazedoxifene reversed both changes in | 4749 SHI et al.