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Breast cancer cells are usually sensitive to several chemotherapeutic regimens, but they can develop chemoresistance after prolonged exposure to cytotoxic drugs, acquiring a more aggressive phenotype. Drug resistance might involve the multi-drug resistance (MDR) 1 gene, encoding a transmembrane glycoprotein p-170 (P-gp), which antagonizes intracellular accumulation of cytotoxic agents, such as doxorubicin. We previously demonstrated that type 2 cyclooxygenase (COX-2) inhibitors can reverse the chemoresistance phenotype of a medullary thyroid carcinoma cell line by inhibiting P-gp expression and function. The aim of our study was to investigate the role of COX-2 inhibitors in modulating chemoresistance in a human breast cancer cell line, MCF7. MCF7 cells, expressing COX-2 but not MDR1, were treated with increasing doses of doxorubicin, and they became chemoresistant after 10 days of treatment, in association with MDR1 expression induction. This effect was reversed by doxorubicin withdrawal and prevented by co-incubation with N-[2-(cyclohexyloxy)4-nitrophenyl]-methanesulfonamide (NS-398), a selective COX-2 inhibitor. Treatment with NS-398 alone did not influence cell viability of a resistant MCF7 cell clone (rMCF7), but sensitized rMCF7 cells to the cytotoxic effects of doxorubicin. Moreover, treatment with NS-398 significantly reduced MDR1 expression in rMCF7 cells. Doxorubicin-induced membrane P-gp expression and function was also greatly impaired. Our data therefore support the hypothesis that COX-2 inhibitors can prevent or reduce the development of the chemoresistance phenotype in breast cancer cells by inhibiting P-gp expression and function.

Owing to the heterogeneity of neuroendocrine neoplasms (NENs), the availability of reliable circulating markers is critical for improving diagnostics, prognostic stratification, follow-up and definition of treatment strategy. This review is focused on chromogranin A (CgA), a hydrophilic glycoprotein present in large dense core vesicles of neuroendocrine cells. Despite being long identified as the most useful NEN-related circulating marker, clinical application of CgA is controversial. CgA assays still lack standardization, thus hampering not only clinical management but also the comparison between different analyses. In the diagnostic setting, clinical utility of CgA is limited as hampered by (a) the variety of oncological and non-oncological conditions affecting marker levels, which impairs specificity; (b) the fact that 30–50% of NENs show normal CgA, which impairs sensitivity. Regarding the prognostic phase, there is prospective evidence which demonstrates that advanced NENs secreting CgA have poorer outcome, as compared with those showing non-elevated marker levels. Although the identification of cut-offs allowing a proper risk stratification of CgA-secreting patients has not been performed, this represents the most important clinical application of the marker. By contrast, based on prospective studies, the trend of elevated circulating CgA does not represent a valid indicator of morphological evolution and has therefore no utility for the follow-up phase. Ultimately, current knowledge about the role of the marker for the definition of treatment strategy is poor and is limited by the small number of available studies, their prevalent retrospective nature and the absence of control groups of untreated subjects.

It is debated if acromegalic patients have an increased risk to develop malignancies. The aim of the present study was to assess the standardized incidence ratios (SIRs) of different types of cancer in acromegaly on a large series of acromegalic patients managed in the somatostatin analogs era. It was evaluated the incidence of cancer in an Italian nationwide multicenter cohort study of 1512 acromegalic patients, 624 men and 888 women, mean age at diagnosis 45 ± 13 years, followed up for a mean of 10 years (12573 person-years) in respect to the general Italian population. Cancer was diagnosed in 124 patients, 72 women and 52 men. The SIRs for all cancers was significantly increased compared to the general Italian population (expected: 88, SIR 1.41; 95% CI, 1.18–1.68, P < 0.001). In the whole series, we found a significantly increased incidence of colorectal cancer (SIR 1.67; 95% CI, 1.07–2.58, P = 0.022), kidney cancer (SIR 2.87; 95% CI, 1.55–5.34, P < 0.001) and thyroid cancer (SIR 3.99; 95% CI, 2.32–6.87, P < 0.001). The exclusion of 11 cancers occurring before diagnosis of acromegaly (all in women) did not change remarkably the study outcome. In multivariate analysis, the factors significantly associated with an increased risk of malignancy were age and family history of cancer, with a non-significant trend for the estimated duration of acromegaly before diagnosis. In conclusion, we found evidence that acromegaly in Italy is associated with a moderate increase in cancer risk.

Somatostatin (SRIF) analogs have been employed in medical therapy of non-functioning pituitary adenomas (NFA), with contrasting results. Previous evidence showed that SRIF can exert its antiproliferative effects by reducing vascular endothelial growth factor (VEGF) secretion and action, and that VEGF expression may be related to pituitary tumor growth. The aim of our study was to clarify the possible effects of a multireceptor SRIF ligand on VEGF secretion and cell proliferation in human NFA primary cultures. We assessed the expression of SRIF receptors (SSTR1–5), the in vitro effects on VEGF secretion, and on cell viability of SRIF and of the stable SRIF analog pasireotide (SOM230), which activates SSTR1, 2, 3, and 5. Twenty-five NFA were examined by RT-PCR for expression of α-subunit, SSTR, VEGF, and VEGF receptors 1 (VEGF-R1) and 2 (VEGF-R2). Primary cultures were tested with SRIF and with pasireotide. All NFA samples expressed α-sub, VEGF and VEGFR-1 and 2, while SSTR expression pattern was highly variable. Two different groups were identified according to VEGF secretion inhibition by SRIF. VEGF secretion and cell viability were reduced by SRIF and pasireotide in the ‘responder’ group, but not in the ‘non-responder’ group, including NFA expressing SSTR5. SRIF and pasireotide completely blocked forskolin-induced VEGF secretion. In addition, SRIF and pasireotide completely abrogated the promoting effects of VEGF on NFA cell viability. Our data demonstrate that pasireotide can inhibit NFA cell viability by inhibiting VEGF secretion, and suggest that the multireceptor-SSTR agonist pasireotide might be useful in medical therapy of selected NFA.