Impact of the putative cancer stem cell markers and growth factor receptor expression on the sensitivity of ovarian cancer cells to treatment with various forms of the HER inhibitors and cytotoxic drugs

Increased expression and activation of human epidermal growth factor receptor (EGFR) and HER-2 have been reported in numerous cancers. The aim of this study was to determine the sensitivity of a large panel of human ovarian cancer cell lines (OCCLs) to treatment with various forms of small molecule tyrosine kinase inhibitors (TKIs) and cytotoxic drugs. The aim was to see if there was any association between the protein expression of various biomarkers including three putative ovarian cancer stem cell (CSC) markers (CD24, CD44, CD117/c-Kit), P-glycoprotein (P-gp), and HER family members and response to treatment with these agents. The sensitivity of 10 ovarian tumour cell lines to the treatment with various forms of HER TKIs (gefitinib, erlotinib, lapatinib, sapitinib, afatinib, canertinib, neratinib), as well as other TKIs (dasatinib, imatinib, NVP-AEW541, crizotinib) and cytotoxic agents (paclitaxel, cisplatin and doxorubicin), as single agents or in combination, was determined by SRB assay. The effect on these agents on the cell cycle distribution, and downstream signaling molecules and tumour migration were determined using flow cytometry, western blotting, and the IncuCyte Clear View cell migration assay respectively. Of the HER inhibitors, the irreversible pan-TKIs (canertinib, neratinib and afatinib) were the most effective TKIs for inhibiting the growth of all ovarian cancer cells, and for blocking the phosphorylation of EGFR, HER-2, AKT and MAPK in SKOV3 cells. Interestingly, while the majority of cancer cells were highly sensitive to treatment with dasatinib, they were relatively resistant to treatment with imatinib (i.e., IC50 >10 µM). Of the cytotoxic agents, paclitaxel was the most effective for inhibiting the growth of OCCLs, and of various combinations of these drugs, only treatment with a combination of NVP-AEW541 and paclitaxel produced a synergistic or additive anti-proliferative effect in all three cell lines examined (i.e., SKOV3, Caov3, ES2). Finally, of the TKIs, only treatment with afatinib, neratinib and dasatinib were able to reduce the migration of HER-2 overexpressing SKOV3 cells. We did not find any significant association between the expression of putative ovarian CSC marker, HER family members, c-MET, ALK, and IGF-IR and the response to the irreversible HER TKIs. Our results support the need for further investigations of the therapeutic potential of these irreversible HER family blockers in ovarian cancer, and the therapeutic potential of dasatinib when used in combination with the inhibitors of the HER family members in ovarian cancer

Correlation of elevated levels of lipoprotein(a), high-density lipoprotein and low-density lipoprotein with severity of preeclampsia: a prospective longitudinal study

The aim of this study was to examine a possible association between the levels of total serum cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL) and lipoprotein(a), and the development of severe preeclampsia. We measured the levels of these lipoproteins in a prospective observational longitudinal cohort study that recruited 50 third-trimester pregnant women with mild preeclampsia at the time of recruitment. Two assessments were performed; the first measurement was at 29–31 weeks of pregnancy (at recruitment), and the second took place 4 weeks later. Patients with BMI 30, those  35 years of age were not included in the study. Eight mildly preeclamptic women developed severe preeclampsia within 4 weeks. In these patients, lipoprotein(a) level showed a twofold increase. A serum lipoprotein(a) level > 40.5 mg/dL in a mildly preeclamptic patient predicted the development of severe preeclampsia later on in the pregnancy, whereas a serum lipoprotein(a) level > 52.5 mg/dL was a marker of severity with high sensitivity and specificity. We suggest through our results that that lipoprotein(a) level correlates with the severity of the disease.IMPACT STATEMENT What is already known on this subject? Changes in blood lipids have been reported in preeclampsia. Abnormal lipoprotein levels are thought to play a role in the pathophysiology of the disease. What the results of this study add? In this study, we showed that a serum lipoprotein(a) level >40.5 mg/dL in a mildly preeclamptic patient predicted the development of severe preeclampsia later on in the pregnancy, whereas a serum lipoprotein(a) level >52.5 mg/dL was a marker of severity with high sensitivity and specificity. What the implications are of these findings for clinical practice and/or further research? Our results suggest that blood lipids, and especially lipoprotein(a), are involved in the pathogenesis of preeclampsia. The lipoprotein(a) level correlates with the severity of the disease. Hence, lipoprotein(a) could be used as a predictor of severe preeclampsia and a marker of the severity of preeclampsia. This should be validated through prospective studies recruiting an adequate sample size