Confirming whether novel rhein derivative 4a induces paraptosis-like cell death by endoplasmic reticulum stress in ovarian cancer cells.

Ovarian cancer is the leading cause of death among gynecologic cancer patients. Although platinum-based chemotherapy as a frontline treatment for ovarian cancer has been widely used in clinical settings, its clinical efficacy is not satisfactory due to the resistance of ovarian cancer cells to apoptosis. Therefore, it is of great significance to induce non-apoptotic programed cell death patterns, such as paraptosis, in ovarian cancer. In this study, we aimed to explore the potential anticancer mechanisms of novel rhein derivative 4a, which was modified with rhein as a lead compound. The results showed that a wide range of vacuoles from the endoplasmic reticulum and mitochondria appeared in ovarian SKOV3, SKOV3-PM4, and A2780 cells treated with derivative 4a, and the cell death caused by derivative 4a is a type of non-apoptotic and non-autophagic death, which is caused by expansion and damage of the endoplasmic reticulum or mitochondria, showing the characteristics of para-apoptotic death. Furthermore, derivative 4a stimulated the unfolded protein reaction of ovarian cancer cells by upregulating the expression of Bip78 and activating the PERK-eIF2α-ATF4 pathways. Notably, rhein derivative 4a-induced cell death was positively correlated with activation of p38, ERK, and JNK, and negatively correlated with Alix, a known protein that inhibits paraptosis. In addition, derivative 4a treatment also induced G2/M phase arrest in ovarian cancer cells. Taken together, our study reveals that derivative 4a induces paraptosis, and this finding can serve as a basis in developing a new strategy for the treatment of antiapoptotic ovarian cancer.

[Experimental investigation of hepatic arterial embolism treatment with microsphere encapsulation of adenovirus with HSV-TK gene].

OBJECTIVE: To evaluate the suitability of the biodegradable microsphere encapsulation of adenovirus as a targeting vector for gene therapy of hepatocellular carcinoma. METHODS: Technique of homologous recombination in bacteria was applied to generate recombinant adenovirus with HSV-TK gene. After obtained the resulting recombinant adenovirus, the solution evaporation method was applied to encapsulate the recombinant adenovirus in poly (lactic/glycolic acid) (PLGA) copolymer. The Wistar rat implantation hepatocellular carcinoma model was set up by inserting the W256 tumor solid piece into Wistar rat's liver. Seven days after implantation on liver, the rats were injected through the proper hepatic artery. All of the rats were divided randomly into five groups: control group (Z1 group); normal saline group (Z2 group), AdEasy-GFP-TK group (Z3 group); placebo PLG microspheres group (Z4 group); PLG microspheres encapsulation of AdEasy-GFP-TK group (Z5 group). All of the proper hepatic arteries were ligated except the rats in Z1 group, following by injecting GCV intraperitoneously. The volume and the weight changes of tumor and the life time of the rats were measured. The in situ hybridization was performed to determinate the HSV-TK gene's transfection. RESULTS: The growth inhibition of tumor and the mean life length in Z5 group was superior to other groups. The expression of HSV-TK was observed in Z3 group and Z5 group by hybridization in situ. CONCLUSION: Genes for gene therapy could transfected into cells of hepatocellular carcinoma efficiently through the proper hepatic artery injection with recombinant adenovirus encapsulated in PLG microsphere. This could improve the effect of gene therapy remarkably.

[Expression of MOST-1 mRNA in bone marrow mononuclear cells from patients with acute lymphoblastic leukemia].

OBJECTIVE: To investigate the MOST-1 mRNA expression in bone marrow (BM) mononuclear cells in children with acute lymphoblastic leukemia, and to explore its association with immunophenotype and treatment response. METHODS: Semiquantitative RT-PCR was employed to study the MOST-1 mRNA expression in BM mononuclear cells separated by Ficoll density gradient method. The MOST-1 expression levels were represented by the ratio of MOST-1 band pixels against its corresponding housekeeping gene beta-actin mRNA band pixels determined by GDS8000 densitometry and GelWork-1 analysis software. The PCR product was eluted and sequenced, and its sequence was confirmed by Pairwise BLAST search. RESULTS: A total of 17 children with acute lymphoblastic leukemia were studied. MOST-1 mRNA was exclusively expressed in the mononuclear cells from 3 patients with ALL-L3 type. However, there was no MOST-1 mRNA expression in other 14 children with ALL-L1 or ALL-L2, irrespective of their initial peripheral WBC count and blast cell percentage in peripheral blood and bone marrow. The MOST-1 mRNA expression levels in two of the ALL-L3 patients with higher blast cell percentages in peripheral blood and bone marrow were 3- and 2-fold respectively as compared with that in the third ALL-L3 child with lower initial blast cell load. MOST-1 mRNA expression was no longer detected in the two ALL-L3 children after complete remission with combination chemotherapy. CONCLUSION: MOST-1 was expressed in the bone marrow mononuclear cells in patients with ALL-L3, and its expression level was somewhat related to tumor cell burden. It might be implicated in the leukemogenesis of ALL-L3 and might serve as an indicator of tumor burden and thus a useful guide for clinical management.