Abstract Purpose Primary liver disease is one of the major health problems in the world, and the prognosis of liver cancer is very poor. Liver cancer cells develop strong resistance to clinical chemotherapy drugs, leading to repeated liver cancer. Materials and Methods RNA-sequence was applied to related signal pathways that significantly altered. Flow cytometry and Western blot were performed to detect the changes of cell cycle, apoptosis and MAPK pathways. Immunofluorescence and flow cytometry were used to detect changes in cell mitochondrial membrane potential and intracellular ROS levels. Western blot, immunofluorescence, qRT-PCR and mCherry-GFP-LC3 were used to detect the effect of autophagy. Western blot and qRT-PCR were utilized to detect the effect of ER Stress. Results EM-6 is a novel monomer purified from Elephantopus mollis H.B.K. Mechanistically, compared with cisplatin (CDDP), EM-6 significantly inhibited the proliferation of human hepatocellular cancer cell lines and had less toxicity to human normal epithelial cells. EM-6 can induce mitochondrial membrane potential disruption, which leads to the accumulation of ROS, S-phase arrest and activation of the IRE1α-ASK1-JNK/p38 pathway to promote apoptosis in Huh-7 cells. In addition, EM-6 blocked protective autophagy by inhibiting the initiation of autophagy, and inhibiting the formation of autophagolysosomes triggered Huh-7 cell apoptosis. Conclusion Taken together, our findings suggest that EM-6 activates mitochondrial apoptosis through the ROS/MAPK pathway and promotes the activation of ER stress and the inhibition of autophagic flux to exacerbate apoptosis. These studies demonstrated the promising future of EM-6 in the clinical treatment of hepatocellular cancer.

BACKGROUND:EM-2, a natural sesquiterpene lactone isolated from Elephantopus mollis H.B.K., showed a good anti-breast cancer effect when combined with epirubicin (EPI). However, its synergistic sensitization mechanism remains unclear.PURPOSE:This study aimed to determine the therapeutic effect and possible synergistic mechanism of EM-2 with EPI in vivo and in vitro and to provide an experimental basis for the treatment of human breast cancer.METHODS:Cell proliferation was measured with MTT and colony formation assays. Apoptosis and reactive oxygen species (ROS) levels were examined through flow cytometry, and the expression levels of proteins related to apoptosis, autophagy, endoplasmic reticulum stress, and DNA damage were detected through Western blot analysis. Moreover, the caspase inhibitor Z-VAD-FMK, autophagy inhibitors bafilomycin A1 and chloroquine, ER stress inhibitor 4-phenylbutyric acid, and ROS scavenger N-acetyl cysteine were applied to verify signaling pathways. Breast cancer cell lines were used to evaluate the antitumor functions of EM-2 and EPI in vitro and in vivo.RESULTS:We demonstrated that in MDA-MB-231 and SKBR3 cells, the IC50 of EPI combined with EM-2 (IC20) was 37.909 and 33.889 times lower than that of EPI alone, respectively. Further study verified that in EPI-resistant lines (MDA-MB-231/EPI), the IC50 of EPI combined with EM-2 (IC20) was 26.305 times lower than that of EPI alone. Mechanistically, EM-2 could reverse the protective effect of EPI against autophagy in SKBR3 and MDA-MB-231 cells. EM-2 and EPI could trigger ER stress. When EM-2 and EPI were used in combination, ER stress was continuously activated, and ER stress-mediated apoptosis was induced. Meanwhile, EM-2 combined with EPI promoted DNA damage then induced apoptosis. In vivo, the volume of breast cancer xenografts in the combination group was smaller than that in the control, EM-2, and EPI groups. Immunohistochemical experiments demonstrated that the combination of EM-2 and EPI could block autophagy and promote ER stress in vivo.CONCLUSION:EM-2 enhances the sensitivity of MDA-MB-231, SKBR3, and EPI-resistant cells to EPI.

Squamocin, an annonaceous acetogenin isolated from plants in the Annonaceae family, has antitumour activity. In this study, we report that Sq-2, a biotinylated squamocin monomer, has a favorable antitumour effect on MDA-MB-231 and SKBR3 breast cancer cells in vitro. MTT assays show that Sq-2 has a better antitumour effect on MDA-MB-231 cells than Sq-5 and Sq-6. Furthermore, RNA-Seq and KEGG enrichment analyses reveal that Sq-2 activates the MAPK signaling pathway, and results of western blot analysis demonstrate that Sq-2 activates the JNK and p38 pathways in MDA-MB-231 and SKBR3 cells. Flow cytometry and western blot analysis reveal that Sq-2 induces cell apoptosis by increasing the expressions of cleaved Caspase-3 and cleaved PARP as well as the ratio of Bax/Bcl-2. Inhibition of the Caspase family by Z-VAD-FMK attenuates the viability of MDA-MB-231 cells, indicating that Sq-2 induces apoptosis in a Caspase-dependent manner. Additionally, pretreatment with the p38 inhibitor SB203580 or JNK inhibitor SP600125 partially reverses the increase in the apoptosis rate and decrease in cell viability prompted by Sq-2. Furthermore, Sq-2 treatment decreases the expression level of CyclinD1 and increases the expression levels of p21, p27, CyclinA1, and CDK2, causing S-phase arrest in MDA-MB-231 and SKBR3 cells. Further study indicates that Sq-2 stimulates autophagy in MDA-MB-231 and SKBR3 cells, and inhibition of autophagy by bafilomycin A1 increases cell viability and promotes cell survival. Sq-2, a novel biotin-squamocin compound, shows a significant inhibitory effect on the propagation of SKBR3 and MDA-MB-231 breast cancer cells. Furthermore, Sq-2 treatment not only induces S-phase arrest and activates the JNK and p38 pathways to trigger apoptosis but also causes autophagy to promote apoptosis in MDA-MB-231 and SKBR3 cells. .

乳腺癌是全球最常见的癌症之一,严重威胁妇女健康.目前乳腺癌的治疗方法包括手术、化疗、放疗、内分泌治疗及分子靶向治疗等,其中利用铁死亡治疗乳腺癌是一种有前景的治疗策略.铁死亡是一种受调控的细胞死亡形式,其特征是铁依赖性的脂质过氧化物的积累.铁死亡与乳腺癌的发展密切相关,诱导铁死亡能抑制乳腺癌细胞增殖、侵袭和迁移,降低其对化疗药物的耐药性、增强其对放疗的敏感性.因此,诱导乳腺癌发生铁死亡是一种具有潜力和价值的治疗策略.

乳腺结节是女性常见疾病，部分结节有可能是乳腺恶性肿瘤。随着中国肥胖人口比例的增加，肥胖带来的健康问题日益凸显，减重手术也越来越频繁地走进公众视野。减重手术能够持续且稳定地维持体重减轻、治愈或改善肥胖相关的代谢合并症，对于肥胖合并2型糖尿病（type 2 diabetes mellitus,T2DM）的疗效优于传统药物治疗 [1] 。我国学者经多因素分析指出，肥胖是乳腺癌发病的独立危险因素 [2] ，

Background: Paris polyphylla is a traditional Chinese medicinal herb that has been used as a haemostatic, antimicrobial and anticancer agent. Gastric cancer (GC) is a global health problem, with more than 1 million people newly diagnosed with gastric cancer worldwide each year.Methods: The MTT and colony formation assay were used to test the anti-proliferative effects of PP-26 on MGC-803 and BGC-823 cells. Flow cytometry assays, Hoechst 33258 staining assay and Caspase inhibitor Z-VAD-FMK were used to test apoptosis. JC-1 staining used to measure changes in mitochondrial membrane potential and western blot analysis were used to test apoptotic and PI3K/Akt pathway related proteins.Results: PP-26 had a dose-dependent inhibitory effect on the proliferation of MGC-803 and BGC-823 cells, but had no obvious anti-proliferative effect on normal liver LO2 cells and normal embryonic kidney HEK-293 cells. Additionally, PP-26 induced typical apoptotic morphological changes, such as nuclear pyknosis, nuclear cracking and apoptotic bodies. Moreover, PP-26 induced a decrease in mitochondrial membrane potential. And PP-26 modulated the expression of Bcl-xL, Mcl-1, Bax, caspase-9/-3 and PARP proteins and induced cell apoptosis through the mitochondrial apoptotic pathway. Next, using an irreversible general caspase inhibitor (Z-VAD-FMK), we confirmed the activation of the mitochondrial apoptotic pathway induced by PP-26. Furthermore, PP-26 inhibited the phosphorylation of Akt and GSK-3β. The inhibition of Akt protein activated the mitochondrial apoptotic pathway.Conclusion: Collectively, these results indicated that PP-26 inhibited the proliferation of MGC-803 and BGC-823 cells by inhibiting the Akt signalling pathway and activating the mitochondrial apoptotic pathway.