Investigating the Effects of Dorema hyrcanum Root Extracts on Selective Induction of Programmed Cell Death in Glioblastoma, Ovarian Cancer and Breast Cancer Cell Lines.

BACKGROUND: Despite remarkable advances, cancer has remained the second cause of death, which shows that more potent novel compounds should be found. Ethnobotanical compounds have a long history of treating diseases, and several approved chemotherapeutic compounds were isolated from plants. OBJECTIVE: The research aimed to evaluate the cytotoxic effects of Dorema hyrcanum root extract on ovarian, breast, and glioblastoma cells while examining its selectivity towards normal cells. Additionally, the study is directed to investigate cell death mechanisms, delineate modes of cell death, and explore intracellular ROS production. METHODS: Cytotoxic effects of alcoholic, dichloromethane, and petroleum ether fractions of Dorema hyrcanum were investigated on cancer and normal cells by using MTT assay, and the concentration around IC50 values was used for flow cytometric assessment of apoptosis, evaluation of the expression of selected genes via RT-qPCR and production of ROS. RESULTS: Methanolic extract exhibited the highest cytotoxicity, impacting A2780CP and MDA-MB-231. All fractions showed comparable effects on U251 cells. Notably, extracts displayed higher IC50 values in normal HDF cells, indicating cancer cell specificity. Flow cytometry revealed induction of apoptosis and non-apoptotic death in all three cancer cell lines. QPCR results showed upregulation of related genes, with RIP3K prominently increased in U251 glioblastoma. The DCFH-DA assay demonstrated ROS induction by the PE fraction exclusively in A2780CP cells after 30 minutes and up to 24 hours. CONCLUSION: Dorema hyrcanum root extracts exhibited potent anti-tumor effects against all studied cell lines. The methanolic extract demonstrated the highest cytotoxicity, particularly against A2780CP and MDA-MB-231 cells. Importantly, all fractions displayed selectivity for cancer cells over normal HDF cells. Unique modes of action were observed, with the petroleum ether fraction inducing significant non-apoptotic cell death. These findings suggest promising therapeutic potential for Dorema hyrcanum in cancer treatment with subject to further mechanistic studies.

Corrigendum: PHGDH Is Upregulated at Translational Level and Implicated in Platin-Resistant in Ovarian Cancer Cells.

[This corrects the article DOI: 10.3389/fonc.2021.643129.].

PHGDH Is Upregulated at Translational Level and Implicated in Platin-Resistant in Ovarian Cancer Cells.

BACKGROUND: Platinum-based chemotherapy is the first line option for ovarian cancer. The development of resistance to such chemotherapy results in treatment failure, while the underlying mechanisms are poorly understood. METHODS: Clinical samples were collected from Shengjing Hospital of China Medical University. MTT assay was used to see the proliferation and chemoresistance of ovarian cancer cells. Transwell migration and Matrigel invasion assays was used to see the invasion ability of ovarian cancer cells. In addition, polysome profiling and tissue microarray and immunohistochemical staining were also used. The statistical significance of the difference was analyzed by ANOVA and post hoc Dunnett's test. RESULTS: PHGDH is the first enzyme responsible for serine biosynthesis pathway. The current study demonstrated that PHGDH is upregulated in platin-resistant ovarian cancer cells and tissues at the protein level. Importantly, knockdown of PHGDH suppressed, while overexpression of PHGDH increased the survival upon cisplatin exposure, invasiveness and spheroid formation of ovarian cancer cells. The current study demonstrated that PHGDH translation was upregulated in platin-resistant ovarian cancer. In addition, our study provided evidence that LncRNA RMRP (RNA Component of Mitochondrial RNA Processing Endoribonuclease) was upregulated in platin-resistant ovarian cancer, which promoted enrichment of RNA binding protein DDX3X (DEAD-Box Helicase 3 X-Linked) on the PHGDH mRNA to promote its translation. CONCLUSION: Collectively, the current study described that PHGDH was upregulated and conferred resistance of ovarian cancer cells to cisplatin, suggesting that cisplatin resistance could be overcome by targeting PHGDH. Our study also provided evidence that differential PHGDH protein expression was defined by its translation, and RNA binding protein DDX3X and LncRNA RMRP are regulators of its translation.

PIPAC-OV3: A multicenter, open-label, randomized, two-arm phase III trial of the effect on progression-free survival of cisplatin and doxorubicin as Pressurized Intra-Peritoneal Aerosol Chemotherapy (PIPAC) vs. chemotherapy alone in patients with platinum-resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer.

BACKGROUND: Recurrent, platin-resistant ovarian cancer (rPROC) has a poor survival. Even with the AURELIA trial, which is the best available treatment today, progression-free survival (PFS) is still only 6.7 months from the start of the second-line chemotherapy. Innovative, effective therapies are urgently needed. Pressurized Intra-Peritoneal Aerosol Chemotherapy (PIPAC) is a novel drug delivery system for administering drugs into the abdomen. PIPAC with cisplatin and doxorubicin (PIPAC C/D) may be safely used at an intraperitoneal dose of 10.5 mg/m2 and 2.1 mg/m2, respectively. Systemic toxicity of this therapy is low. In a phase II trial with 53 women, 62 % patients had an objective tumor response. Tumor regression on histology was observed in 76 % patients who underwent all three PIPACs. Randomized phase III studies are now required to evaluate the effect of PIPAC C/D compared to other standard treatments (sequential or simultaneous applications with systemic chemotherapy). METHODS: The present phase III study is a prospective, open, randomized, multicentric pivotal trial. A total of 244 patients will be randomly assigned (1:1) to the control (A) or to the experimental (B) group. Group A: Systemic palliative chemotherapy, physician's best choice (monotherapy consisting of pegylated liposomal doxorubicin or topotecan or gemcitabine or paclitaxel weekly. Bevacizumab can be used in combination with paclitaxel, topotecan, or pegylated liposomal doxorubicin). Group B: Intraperitoneal chemotherapy, 3×PIPAC C/D, performed every 6 weeks. Combination with systemic therapy is not allowed. Treatment is continued until disease progression, death, or patient refusal. In case of progression, no recommendation for further therapy is given by protocol. Patients are allowed to receive PIPAC C/D or systemic chemotherapy after study termination. The primary endpoint is PFS (according to RECIST v1.1) or death from any cause. The co-primary endpoint is the health-related quality of life (HRQoL) measured as the global health status (GHS, QLQ-30 of EORTC). Secondary outcomes comprise overall survival, safety (CTCAE 5.0), and tumor response according to peritoneal regression grading score (PRGS). DISCUSSION: We expect PIPAC C/D to control peritoneal disease and preserve the QoL on this subset of patients. TRIAL REGISTRATION: The EudraCT number 2018-003664-31.