The progress and prospect of sentinel lymph node mapping in endometrial carcinoma.

Sentinel lymph node (SLN) refers to the initial site of the lymphatic drainage from a primary tumor area. Identifying the SLN and analyzing tumor involvement can predict the status of the remaining lymph nodes. Accordingly, sentinel lymph node mapping (SLN mapping) has been brought up and widely applied to cancer therapy for its illuminating role in clinical lymph node resection. Sufficient information to guide surgical pathological staging and adjuvant treatment in endometrial cancer can be rendered by SLN mapping, hence minimizing surgery injury and reducing the incidence of complications. Evidence suggests that using SLN mapping does not affect progression-free survival (PFS) and overall survival (OS) of endometrial cancer patients. Furthermore, there is increasing evidence that using SLN mapping has a high detection rate (DR), sensitivity, and negative predictive value (NPV) for patients with early-stage lower-risk endometrial cancer. This review aims to systematically summarize the advances and application prospects of SLN mapping in endometrial cancer, with an expectation of furnishing reference for the clinical application.

Understanding endometriosis from an immunomicroenvironmental perspective.

ABSTRACT: Endometriosis, a heterogeneous, inflammatory, and estrogen-dependent gynecological disease defined by the presence and growth of endometrial tissues outside the lining of the uterus, affects approximately 5-10% of reproductive-age women, causing chronic pelvic pain and reduced fertility. Although the etiology of endometriosis is still elusive, emerging evidence supports the idea that immune dysregulation can promote the survival and growth of retrograde endometrial debris. Peritoneal macrophages and natural killer (NK) cells exhibit deficient cytotoxicity in the endometriotic microenvironment, leading to inefficient eradication of refluxed endometrial fragments. In addition, the imbalance of T-cell subtypes results in aberrant cytokine production and chronic inflammation, which contribute to endometriosis development. Although it remains uncertain whether immune dysregulation represents an initial cause or merely a secondary enhancer of endometriosis, therapies targeting altered immune pathways exhibit satisfactory effects in preventing disease onset and progression. Here, we summarize the phenotypic and functional alterations of immune cells in the endometriotic microenvironment, focusing on their interactions with microbiota and endocrine and nervous systems, and how these interactions contribute to the etiology and symptomology of endometriosis.

Squamous cell carcinoma in mature cystic teratoma of the ovary induced by human papillomavirus 16 infection: A case report and literature review.

RATIONALE: Mature cystic teratoma is the most common ovarian germ cell tumor. The malignant transformation of ovarian mature cystic teratoma (MCT) is very rare, but the prognosis is poor. We present a case of ovarian mature cystic teratoma with human papillomavirus infection and malignant transformation into ovarian squamous cell carcinoma (SCC). The occurrence of this case may prove that high-risk human papillomavirus infection is a pathogenic factor inducing malignant transformation of mature cystic teratoma to SCC. PATIENT CONCERNS: A 38-year-old woman with a solid cystic mass of 8 cm on the right ovary, and human papillomavirus (HPV) test of her cervix showed HPV-16 infection. DIAGNOSIS: The transvaginal ultrasound was performed, and there was a cystic solid mass of 5.9 × 4.5 × 5.5 cm in the right adnexal area with unclear cystic fluid and rich blood flow signals in the capsule wall. HPV test of cervix showed HPV-16 infection. Diagnostic suspicion: cystic teratoma. INTERVENTION: The patient signed an laparoendoscopic surgery was performed to remove the right ovarian mass. Intraoperative pathology consultation revealed the malignant transformation of mature teratoma of the right ovary and the formation of squamous or adeno-SCC. We performed laparoscopic comprehensive surgical staging (hysterectomy, bilateral salpingo-oophorectomy, omentectomy, appendectomy, pelvic and para-aortic lymph node dissection) were made. OUTCOMES: The operation was successful and the postoperative recovery was smooth, was discharged 7 days after operation. Now the patient is recovering well and is continuing chemotherapy as planned. CONCLUSION: HR-HPV infection might be a causal factor for inducing malignant transformation of ovarian MCT to SCC, and the Jumping metastasis of lymph nodes may be the characteristic of SCC-MCT, but further verification is still needed.

Targeting the tumor microenvironment by an enzyme-responsive prodrug of tubulin destabilizer for triple-negative breast cancer therapy with high safety.

In response to the long-term potential toxicity concerns of tubulin destabilizer, an enzyme-responsive prodrug therapy for triple-negative breast cancer was developed based on the different ß-glucuronidase levels between tumor and normal tissues in this study. All the prodrugs synthesized herein showed remarkable stability in phosphate buffer and bovine serum solution, among which 17a was found to be more susceptible to enzymatic cleavage. 17a exhibited excellent selectivity between the in vitro antiproliferative activities against ß-glucuronidase-pretreated and -untreated cancer cells (IC50 (+Enz) = 8.9-15.7 nM, IC50 (-Enz) > 50 µM), along with favorable liver microsomal metabolic stability and improved aqueous solubility. Furthermore, as a candidate prodrug 17a showed potent antitumor efficacy in MDA-MB-231 xenograft mouse model without causing perceptible injury to organs. Importantly, 17a exhibited superior safety profiles with higher LD50 value and no perceivable cardiotoxicity, which was a major dose-limiting adverse effect for the parent compound 1. These salient toxicity-reduced effects of 17a would merit further in-depth assessment of this compound for preclinical therapeutic usages.

Discovery of novel celastrol-triazole derivatives with Hsp90-Cdc37 disruption to induce tumor cell apoptosis.

To enhance the disruption of Hsp90-Cdc37, we designed and synthesized a series (27) of CEL-triazole derivatives. Most of the target compounds showed enhanced anti-proliferative activity on four cancer cell lines (MDA-MB-231, MCF-7, HepG2 and A459). Among them, compound 6 showed the best anti-proliferation (IC50 = 0.34 ± 0.01 µM) on MDA-MB-231. Pharmacological studies had found that compound 6 showed a higher ability to disrupt Hsp90-Cdc37 interaction in cells and inhibited the expression of the key Hsp90-Cdc37 clients in a concentration-dependent manner. Further studies indicated that an enhanced covalent binding between compound 6 and thiols (cysteine) might be one of the reasons for the increased activity. Furthermore, compound 6 arrested cells in the G0/G1 phase and induced tumor cell apoptosis significantly. Overall, for cancer treatment, compound 6 was worth further exploring.

Design, Synthesis, and Activity Evaluation of Novel Acyclic Nucleosides as Potential Anticancer Agents In Vitro and In Vivo.

In the present work, 103 novel acyclic nucleosides were designed, synthesized, and evaluated for their anticancer activities in vitro and in vivo. The structure-activity relationship (SAR) studies revealed that most target compounds inhibited the growth of colon cancer cells in vitro, of which 3-(6-chloro-9H-purin-9-yl)dodecan-1-ol (9b) exhibited the most potent effect against the HCT-116 and SW480 cells with IC50 values of 0.89 and 1.15 µM, respectively. Furthermore, all of the (R)-configured acyclic nucleoside derivatives displayed more potent anticancer activity compared to their (S)-counterparts. Mechanistic studies revealed that compound 9b triggered apoptosis in the cancer cell lines via depolarization of the mitochondrial membrane and effectively inhibited colony formation. Importantly, compound 9b inhibited the growth of the SW480 xenograft in a mouse model with low systemic toxicity. These results indicated that acyclic nucleoside compounds are viable as potent and effective anticancer agents, and compound 9b may serve as a promising lead compound that merits further attention in future anticancer drug discovery.

Novel Scopoletin Derivatives Kill Cancer Cells by Inducing Mitochondrial Depolarization and Apoptosis.

BACKGROUND: Natural products and their molecular frameworks have been explored as invaluable sources of inspiration for drug design by means of structural modification, computer-aided drug design, and so on. Scopoletin extracting from multiple herbs exhibits potential anti-cancer activity in vitro and in vivo without toxicity towards normal cells. OBJECTIVE: The study aims to obtain new scopoletin derivatives with enhanced anti-cancer activity. We performed chemical structure modification and researched the mechanism of anti-tumor activity. METHODS: In this study, we considered scopoletin as a lead compound, designed and synthesized a series of scopoletin derivatives via introducing different heterocyclic fragments, and their chemical structures were characterized by NMR spectra (1H NMR and 13C NMR) and HRMS(ESI). The antiproliferative activity of target compounds in four cancer cell lines (MDA-MB-231, MCF-7, HepG2, and A549) was determined by the MTT assay. Compound 11b was treated with Ac-cys under different reaction conditions to explore the thiol addition activity of it. The Annexin V/PI and JC-1 staining assay were performed to investigate the anti-tumor mechanism of 11b. RESULTS: Novel compounds 8a-h and 11a-h derivatives of scopoletin were synthesized. Most of the target compounds exhibited enhanced antiproliferative activity against different cancer cells and reduced toxicity towards normal cells. In particular, 11b displayed the optimal antitumor ability against breast cancer MDA-MB- 231 cells with an IC50 value of 4.46 µM. Compound 11b also cannot react with Ac-cys under the experimental condition. When treated with 11b for 24 h, the total apoptotic cells increased from 10.8% to 79.3%. Besides, 11b induced the depolarization of mitochondrial membrane potential. CONCLUSION: Compound 11b was more active than other derivatives, indicating that the introduction of thiophene fragment was beneficial for the enhancement of antitumor effect, and it was also not an irreversible inhibitor based on the result that the α, ß-unsaturated ketones of 11b cannot undergo Michael addition reactions with Accys. Furthermore, studies on the pharmacological mechanism showed that 11b induced mitochondrial depolarization and apoptosis, which indicated that 11b killed cancer cells via a mitochondrial apoptotic pathway. Therefore, in-depth research and structure optimization of this compound is warranted.

Design, synthesis and biological evaluation of novel plumbagin derivatives as potent antitumor agents with STAT3 inhibition.

Based on the structure of signal transducer and activator of transcription 3 (STAT3), a series of 1,4-naphthoquinones derived from plumbagin (PL) with STAT3 inhibition potential were designed, synthesized, and biologically evaluated in vitro against several human cancer cell lines (MDA-MB-231, HepG2 and A549 cells) and three normal cells. The structure-activity relationship (SAR) and molecular docking result showed that the presence of hydroxyl group at C-5 of PL might interact with STAT3 in the form of hydrogen bonds, which is conducive to the binding of this kind structures with STAT3. Among the target compounds, 7a displayed the most potent inhibition against cancer cells and weaker cytotoxicity on normal cells than PL. The western bolting analysis showed that 7a could suppress the phosphorylation of STAT3 as well as the downstream genes instead of affecting its upstream tyrosine kinases (Src and JAK2) levels and p-STAT1 expression. Furthermore, molecular docking indicated that 7a bound to STAT3 more tightly than PL, and it could significantly induce the apoptosis of cancer cells in vitro. All these results may provide reference for the discovery of effective STAT3 inhibitors.

Novel NO-releasing scopoletin derivatives induce cell death via mitochondrial apoptosis pathway and cell cycle arrest.

A series of phenylsulfonyfuroxan-based NO-releasing scopoletin derivatives were designed and synthesized in the study. All target compounds showed significantly improved antiproliferative activity against four cancer cell lines (MDA-MB-231, MCF-7, HepG2 and A459) and lower cytotoxicity toward normal liver LO2 cells. Derivative 47 concentration-dependently inhibited the colony formation of MDA-MB-231 cells. NO-releasing assessment indicated that the intracellular NO level was almost positively correlated with the antiproliferative ability. Compound 47, which released the highest amounts of NO, showed the best potency (IC50 = 1.23 µM) against MDA-MB-231 cells. Mechanism research revealed for the first time that 47 blocked the proliferation of MDA-MB-231 cells by activating mitochondrial apoptosis pathway and arresting cell cycle at G2/M phase. Taken together, as a novel scopoletin derivative, 47 exhibited excellent inhibitory effects against malignant cancer cells and lower toxicity on normal cells. Thus, an in-depth evaluation of 47 to explore its complete therapeutic potential for cancer treatment is warranted.

Discovery of Novel Celastrol Derivatives as Hsp90-Cdc37 Interaction Disruptors with Antitumor Activity.

To develop novel and efficient heat shock protein 90-cell division cycle 37 (Hsp90-Cdc37) interaction disruptors, several lipophilic fragments were introduced into celastrol (CEL) to synthesize 48 new CEL derivatives. Among all the target compounds, 41 was screened with superior antiproliferative activity on related cancer cells (IC50: 0.41-0.94 µM) and 41 could decrease the level of the Hsp90-Cdc37 complex in A549 cells. The capability to disrupt the Hsp90-Cdc37 interaction was stronger than that of CEL. Furthermore, pull-down assay, UV assay, and molecular docking analysis all showed that 41 might disrupt the interaction of the Hsp90-Cdc37 complex by preferentially binding to Cdc37 in cancer cells. Further studies showed that 41 could significantly regulate the levels of Hsp90-Cdc37 clients, thereby inducing the apoptosis of cancer cells. Together, 41 is a novel Hsp90-Cdc37 disruptor by binding to Cdc37 (hydrogen bond and/or covalent bond). Our results may provide reference for the discovery of effective Hsp90-Cdc37 disruptors.

Design, synthesis and antitumor evaluation of novel celastrol derivatives.

On the basis of the hybridization strategy of natural products, a total of 32 novel celastrol hybrids were designed, synthesized and evaluated for their antitumor activities. Most of these derivatives exihibited significant antiproliferative activities compared to celastrol, among which compound 29 displayed the strongest inhibitory capability [IC50 = 0.15 ±â€¯0.03 µM (A549),0.17 ±â€¯0.03 µM (MCF-7), 0.26 ±â€¯0.02 µM (HepG2)], which exhibited equal or superior anti-cancer activities in comparison to 2-cyano-3,12-dioxoolean-1,9 (11)-dien-28-oic acid methyl ester (CDDO-Me). The mechanism of pharmacological research indicated that 29 possessed the ability to disrupt Hsp90-Cdc37 complex which was stronger than celastrol. Meanwhile, compound 29 could induce abnormal regulation of clients (p-Akt and Cdk4) of Hsp90 and cell cycle arrest at G0/G1 phase in a concentration-dependent manner. In addition, compound 29 could also induce cell apoptosis through the death receptor pathway on A549 cells. Taken together, our results demonstrated that 29 might be a promising novel candidate for further druggability research.

[Determination of papaverine in seeds of Papaver somniferum L. and soup of chafing dish by high performance liquid chromatography-fluorescence detection].

A method of reversed-phase high performance liquid chromatography coupled with fluorescence detection was developed for the separation and determination of papaverine in seeds of Papaver somniferum L. and soup of chafing dish. The liquid chromatographic experiment was carried out under the following conditions: the detector was a fluorescence with excitation wavelength at 285 nm and emission wavelength at 355 nm. An RP-C18 column (250 mm x 4.6 mm i.d., 5 microm) was used. The mobile phase was a mixture of methanol and 0.02 mol/L ammonium acetate (70: 30, v/v). The flow rate was 0.8 mL/min. A linear range was obtained from 0.1 ng to 0.1 microg with a good correlation. The lowest detection limit was 0.02 ng. The average recovery of seeds for Papaver somniferum L. was 99.0% - 100.8%. The method is rapid, accurate, sensitive and suitable for the separation and determination of papaverine in foods.

[Determination of xanthones in Swertia mussotii and Swertia franchetiana by high performance liquid chromatography].

A simple and rapid method for simultaneous separation and determination of xanthones in Swertia mussotii and Swertia franchetiana by high performance liquid chromatography has been established. The analysis was performed on a Kromasil C18 column (250 mm x 4.60 mm i.d., 5 microm) (at 20 degrees C) eluted with methanol and 0.1% aqueous phosphoric acid (73: 27 in volume ratio) as mobile phase at a flow rate of 1.0 mL/min and with UV detection at 260 nm. Results showed that xanthones were separated successfully from each other and from other interfering components. There was a good linear relationship between the content of component and its peak area for each xanthone, with the correlation coefficients of 0.999 2 - 0.999 9. The convenient method can be used for quantitative analysis of xanthones.

[Determination of the base contents of liver DNA of rats by reversed-phase high performance liquid chromatography].

The base contents of liver deoxyribonucleic acid (DNA) of rats living at an altitude of 2.3 km were determined by reversed-phase high performance liquid chromatography. At first, 0.05 mol/L KH2PO4(pH 4.0) was used to dissolve the DNA acid hydrolysis products with 8-bromoguanosine (Br8G) as an internal standard. Then the DNA hydrolysis products with Br8G were chromatographed on a Supelcosil LC-18 column with UV detection at 254 nm and eluted by the mobile phase of MeOH-0.05 mol/L KH2PO4(pH 4.0) (20:80, V/V) at the flow rate of 0.8 mL/min. Under these conditions, several bases were separated effectively. From the results, the relatively constant proportions of the bases in DNA were found. The contents were 17.4% of cytosine (C), 28.8% of adenine (A), 23.3% of guanine (G) and 25.3% of thymine (T). RSDs of the determination of these bases were 1.7%, 1.5%, 1.3% and 2.1%, respectively. At the same time the methylation level of liver DNA of the rats determined by the internal standard method was 6.2%.