Jian Li

Repurposing of antipsychotics perphenazine for the treatment of endometrial cancer

Endometrial cancer (EC) is one of the most common and fatal gynecological cancers worldwide, but there is no effective treatment for the EC patients of progesterone resistance. Repurposing of existing drugs is a good strategy to discover new candidate drugs. In this text, perphenazine (PPZ), approved for psychosis therapy, was identified as a potential agent for the treatment of both progesterone sensitive and resistant endometrial cancer for the first time. Specifically, perphenazine exhibited good cell proliferation inhibition in Ishikawa (ISK) and KLE cell lines according to the CCK-8 assay and colony formation assay. It also reduced the cell migration of ISK and KLE cell lines in the light of the transwell migration assay. Annexin-V/PI double staining assay suggested that perphenazine could effectively induce ISK and KLE cell apoptosis. Moreover, results of western blot assay indicated perphenazine obviously inhibited the phosphorylation of Akt. Delightedly, PPZ also could significantly attenuate xenograft tumor growth at both 3 mg/kg and 15 mg/kg in mice without influencing the body weights.

Application Value of Real-Time Ultrasonic Elastograph with Serum Human Epididymis Protein 4, Interleukin-33, and Carbohydrate Antigen 153 in Diagnosis of Early Cervical Cancer

Objective. To explore the application value of real-time ultrasonic elastograph (USE) with serum human epididymis protein 4 HE4, interleukin-33 (IL-33), and carbohydrate antigen 153 (CA153) in the diagnosis of early cervical cancer. Methods. A total of 120 cervical cancer patients treated in our hospital (06, 2019–06, 2021) and meeting the study criteria were screened and divided into the benign group (BG, n = 70) and malignant group (MG, n = 50) according to their final diagnostic results, and healthy females who received physical examination in our hospital in the same period were selected as the control group (CG, n = 60). Patients in the three groups received real-time USE and detection of serum HE4, IL-33, and CA153 so as to analyze the diagnostic value of single examination and combined examination in diagnosing early cervical cancer. Results. The patients’ real-time USE score, Emax, Emean, and elastic fibers were significantly higher in the MG than those in the BG ( P < 0.05 ), and the patients’ real-time USE Emin, stroma ratio and collagen fibers were significantly lower in the MG than those in the BG ( P < 0.05 ); the HE4, IL-33, and CA153 levels were obviously higher in the MG than those in the BG ( P < 0.05 ) and were significantly higher in the BG than those in the CG ( P < 0.05 ); the positive detection rate of combining real-time USE with serum HE4, IL-33, and CA153 was higher than that of single examination, and the diagnostic accuracy rate, sensitivity, specificity, positive predictive value, and negative predictive value of the combined examination were significantly higher than those of single examination ( P < 0.05 ); according to the diagnostic efficacy of single examination and combined examination in diagnosing early cervical cancer by ROC curve, it was combined diagnosis > real-time USE > HE4 > CA153 > IL-33. Conclusion. Combined examination of real-time USE and serum HE4, IL-33, and CA153 has higher diagnostic value in diagnosing early cervical cancer, which can obviously improve the diagnostic accuracy rate of cervical cancer.

Non-interference delivery of Ce6 and DOX in NIR light-responsive liposomes for synergetic cervical cancer therapy

Abstract Multi-model combination treatment of malignant tumors can make up for the shortcomings of single treatment through multi-target and multi-path to achieve more ideal tumor treatment effect. However, the mutual interference of different drugs in the delivery process in vivo and the difficulty of effective drug accumulation in tumor cells are the bottlenecks of combined therapy. To this project, light-responsive liposomes loading doxorubicin (DOX) and chlorin e6 (Ce6) (DOX-Ce6-Lip) without mutual interference were engineered by thin film hydration method. This kind of nano-drug delivery system increased the drugs concentration accumulated in tumor sites through enhanced permeability and retention effect, and reduced the toxic and side effects of drugs on normal tissues in vivo. In addition, after entering the tumor cells, Ce6 produced a large number of reactive oxygen species under 660 nm NIR laser irradiation, which further oxidized the unsaturated fatty acid chain in the liposomes and caused the collapse of the liposomes, thus realizing the stimulus-responsive release of Ce6 and DOX. The concentrations of DOX and Ce6 in the tumor cells rapidly reached the peak and achieved a more effective combination of chemotherapy and photodynamic therapy (PDT). Consequently, DOX-Ce6-Lip followed by 660 nm NIR irradiation achieved an efficient tumor growth inhibition of 71.90 ± 3.14%, indicating the versatile potential of chemotherapy and PDT. In conclusion, this study provides a delivery scheme for drugs with different solubilities and an effectively combined anti-tumor therapy method.

Gain-of-Function Chromatin Remodeling Activity of Oncogenic FOXL2C134W Reprograms Glucocorticoid Receptor Occupancy to Drive Granulosa Cell Tumors

Abstract Adult type ovarian granulosa cell tumors (AGCT) are rare malignancies with the near universal c.C402G (p.Cys134Trp) somatic mutation in FOXL2, a forkhead box family transcription factor important for ovarian function. Relapsed AGCT is incurable, but the mechanism of the unique FOXL2 mutation could confer therapeutic vulnerabilities. To identify FOXL2C134W-dependent pharmacologic synergies, we created and characterized endogenous FOXL2 isogenic AGCT cells and an AGCT tumoroid biobank. A drug screen identified that glucocorticoids promote FOXL2C134W-dependent AGCT growth. Epigenetic investigation revealed that the Cys134Trp mutation exposes latent DNA sequence–specific chromatin remodeling activity in FOXL2. FOXL2C134W-dependent chromatin remodeling activity redirected glucocorticoid receptor chromatin occupancy to drive hyaluronan synthase 2 gene expression and increase extracellular hyaluronan secretion. Treatment of AGCT models with hyaluronidase reduced viability, and dexamethasone rescued this effect. Combinatorial drug–drug interaction experiments demonstrated that dexamethasone antagonizes the potency of paclitaxel, a chemotherapy agent frequently used in the treatment of AGCT. Thus, gain-of-function pioneering activity contributes to the oncogenic mechanism of FOXL2C134W and creates a potentially targetable synergy with glucocorticoid signaling. Significance: Glucocorticoids promote granulosa cell tumor growth via epigenetic coregulation with the disease driver FOXL2C134W, providing mechanistic insight into disease oncogenesis and uncovering a potential treatment strategy.

Discovery of Novel Azaphenothiazine Derivatives to Suppress Endometrial Cancer by Targeting GRP75 to Impair Its Interaction with IP3R and Mitochondrial Ca2+ Homeostasis

Endometrial cancer (EC) is the most common cancer of the female reproductive tract, and there is an urgent need to develop new candidate drugs with good efficacy and safety to improve the survival rate and life quality of EC patients. Herein, a series of new azaphenothiazine derivatives were designed and synthesized and their anti-EC activities were evaluated. Among them, compound