Childhood cancer drugs in China: An overview and comparison of regulatory approvals in China and the United States.

Different from less developed countries, 80% of children with cancers in the United States are cured. Traditional chemotherapy drugs are the mainstay of therapies; new targeted medications have become available recently. Using publicly available data, we created a database of cancer drugs with paediatric malignancy indications approved by 31 October 2020 in China and the United States. We compared numbers, type, indications and listing on the World Health Organization Model List of Essential Medicines for Children (WHO EMLc) between the two countries, assessed the correlation between paediatric indications and cancer incidences, and described evidence supporting approvals of targeted medications in the two settings. Our study showed that by 31 October 2020, 31 and 39 cancer drugs available in China and the United States were approved for use in children, corresponding to 137 and 102 paediatric cancer indications, respectively. About half of these drugs (17 in China and 18 in the United States) were listed on the WHO EMLc. The correlation between indications and burden of disease was higher in the United States (r = 0.68) than China (r = 0.59). More traditional chemotherapy drugs were approved in China (n = 27) than the United States (n = 19). Of 20 targeted childhood anticancer medicines approved in the United States, mainly on the basis of single arm trials (27/32 indications, 84.4%), only four were approved for paediatric indications in China, at a median of 2.8 years after US Food and Drug Administration approval. A harmonised, evidence-based regulatory framework is needed to ensure approvals of needed, safe and efficacious childhood cancer drugs across the world.

Matrine inhibits proliferation and induces apoptosis via BID-mediated mitochondrial pathway in esophageal cancer cells.

Matrine, as a member of Sophora family, is an alkaloid found in plants, and produces plethora pharmacological effects, including anti-cancer effects. However, the mechanism involved remains largely unknown. This study is conducted to investigate the anti-cancer mechanisms of matrine in human esophageal cancer in vitro and in vivo. In human esophageal cancer cell Eca-109, matrine significantly decreased the cell viability in a dose-dependent manner, and induced apoptosis as well as cell cycle arrest in G0/G1 phase by up-regulation of P53 and P21. The expression of several apoptosis-related proteins in cells and tumor tissues were evaluated by Western blot analysis. We found that matrine induced cell apoptosis by down-regulation of the ratio of BCL-2/BID and increasing activation of caspase-9. Further studies indicated that matrine induced apoptosis of Eca-109 was through the mitochondria-mediated internal pathway, but not by death receptor-mediated extrinsic apoptotic pathway, which was confirmed by the fact that Bid translocated from the nucleus to mitochondria during the process of the apoptosis induced by matrine. In vivo study found that matrine effectively inhibited the tumor formation of Eca-109 cells in nude mice. Our study suggests that matrine could serve as a potential novel agent from natural products to treat esophageal cancer.

Decreased monoamine oxidase (MAO) activity and MAO-A expression as diagnostic indicators of human esophageal cancers.

Human esophageal cancer is a common occurring malignancy with high mortality rate partially due to lack of tools for early diagnosis. In this study, we have analysed tumour tissue from 50 cases of primary esophageal cancer. Our studies showed that the activity of monoamine oxidase (MAO) and the expression of MAO-A were strikingly decreased in the tumour tissues of 48 (96%) and 44 (88%) patients, respectively. These results suggest that the activity of MAO and the expression of MAO-A may be used as new diagnostic markers for esophageal cancers.

ß-elemene reverses the drug resistance of lung cancer A549/DDP cells via the mitochondrial apoptosis pathway.

ß-elemene (ß-ELE) is a new anticancer drug extracted from Curcuma zedoaria Roscoe and has been widely used to treat malignant tumors. Recent studies have demonstrated that ß-ELE reverses the drug resistance of tumor cells. To explore the possible mechanisms of action of ß-ELE, we investigated its effects on cisplatin-resistant human lung adenocarcinoma A549/DDP cells. The effects of ß-ELE on the growth of A549/DDP cells in vitro were determined by MTT assay. Apoptosis was assessed by fluorescence microscopy with Hoechst 33258 staining and flow cytometry with Annexin V-FITC/PI double staining. Mitochondrial membrane potential was assessed using JC-1 fluorescence probe and laser confocal scanning microscopy, and intracellular reactive oxygen species levels were measured by 2',7'-dichlorofluorescein-diacetate staining and flow cytometry. Cytosolic glutathione content was determined using GSH kits. The expression of cytochrome c, caspase-3, procaspase-3 and the Bcl-2 family proteins was assessed by western blotting. The results demonstrated that ß-ELE inhibited the proliferation of A549/DDP cells in a time- and dose-dependent manner. Furthermore, ß-ELE enhanced the sensitivity of A549/DDP cells to cisplatin and reversed the drug resistance of A549/DDP cells. Consistent with a role in activating apoptosis, ß-ELE decreased mitochondrial membrane potential, increased intracellular reactive oxygen species concentration and decreased the cytoplasmic glutathione levels in a time- and dose-dependent manner. The combination of ß-ELE and cisplatin enhanced the protein expression of cytochrome c, caspase-3 and Bad, and reduced protein levels of Bcl-2 and procaspase-3 in the A549/DDP lung cancer cells. These results define a pathway of procaspase­3-ß-ELE function that involves decreased mitochondrial membrane potential, leading to apoptosis triggered by the release of cytochrome c into the cytoplasm and the modulation of apoptosis-related genes. The reversal of drug resistance of the A549/DDP cell line by ß-ELE may be derived from its effect in inducing apoptosis.

ß-elemene reverses the drug resistance of A549/DDP lung cancer cells by activating intracellular redox system, decreasing mitochondrial membrane potential and P-glycoprotein expression, and inducing apoptosis.

BACKGROUND: ß-elemene (ß-ELE) injection is a new anticancer drug extracted from Curcuma zedoaria Roscoe that has been widely used to treat malignant tumors. Recent studies show that ß-ELE reverses the drug resistance of tumor cells. To explore the possible mechanisms of ß-ELE, we investigated its effects on cisplatin (DDP)-resistant human lung adenocarcinoma A549/DDP cells. METHODS: The effects of ß-ELE on the growth of A549/DDP cells in vitro were determined by MTT assay. Apoptosis was assessed by fluorescence microscopy with Hoechst 33258 staining, flow cytometry with Annexin V-FITC/propium iodide double staining; mitochondrial membrane potential using JC-1 fluorescence probe and laser confocal scanning microscopy, and intracellular reactive oxygen species levels were measured by 2',7'-dichlorfluorescein-diacetate staining and flow cytometry; and contents of cytosolic glutathione were determined by glutathione assay kits. Intracellular Rhodamine-123 fluorescence intensity was detected by flow cytometry, and the expression of P-glycoprotein (P-gp) was detected by Western blotting. RESULTS: ß-ELE inhibited the proliferation of A549/DDP cells in a time- and dose-dependent manner. Furthermore, ß-ELE enhanced the sensitivity of A549/DDP cells to cisplatin and reversed the drug resistance of A549/DDP cells. Consistent with a role in activating apoptosis, ß-ELE decreased mitochondrial membrane potential, increased intracellular reactive oxygen species concentration and intracellular accumulation of Rhodamine-123, decreased the cytoplasmic glutathione levels and the expression of P-gp in a time- and dose-dependent manner. CONCLUSIONS: These results define a pathway of ß-ELE function that involves decreased mitochondrial membrane potential and P-gp expression activated intracellular redox system, and induced apoptosis leading to reverse drug resistance.