Enhancing tumor response to targeted chemotherapy through up-regulation of folate receptor α expression induced by dexamethasone and valproic acid.

Several folate-drug conjugates are currently undergoing clinical trials for application in oncology. However, the efficacy of folate-targeted therapy strongly depends on the folate receptor (FR) abundance at the surface of cancer cells. Recently, it has been postulated that up-regulation of FRα by means of chemo-sensitizing agents could enhance the anticancer activity of FR-drug conjugates. In this study, we demonstrate in vitro that a combination of dexamethasone (Dexa) and valproic acid (VPA) increases FRα expression selectively at the surface of FR-overexpressing cancer cells. The same stimulation was observed in vivo in KB-tumor xenografts when mice are treated with this combined treatment. This effect is reversible since treatment interruption induces the return of FR expression at basal level. When incubated with Dexa and VPA, the ß-galactosidase-responsive folate-monomethyl auristatin E (MMAE) conjugate, called MGAF, exhibits higher cytotoxic activity on several FR-positive human cancer cell lines, compared to its administration as a single agent. This improved toxicity results from the enhanced concentration of MMAE released within cancer cells after internalization and subsequent enzymatic activation of MGAF. Higher deposition of MMAE is also observed in vivo after up-regulation of FR expression level in tumor xenografts, induced by the prior administration of the Dexa/VPA combination. In this model, MGAF/Dexa/VPA combined therapy results in an 81% inhibition of tumor growth compared to the control group, while MGAF used in monotherapy is inefficient. Since Dexa and VPA are currently used in humans, this finding could be of great interest for further development of folate-drug conjugates, in particular for those that are presently under clinical investigation.

Serotonin and cancer: what is the link?

Serotonin (5-hydroxytryptamine, 5-HT) is a biogenic monoamine that acts as a neurotransmitter in the central nervous system, local mediator in the gut and vasoactive agent in the blood. Serotonin exerts its multiple, sometimes opposing actions through interaction with a multiplicity of receptors coupled to various signalling pathways. In addition to its well-known functions, serotonin has been shown to be a mitogenic factor for a wide range of normal and tumoral cells. Serotonin exhibits a growth stimulatory effect in aggressive cancers and carcinoids more often through 5- HT1 and 5-HT2 receptors. In contrast, low doses of serotonin can inhibit tumour growth via the decrease of blood supply to the tumour, suggesting that the role of serotonin on tumour growth is concentration-dependent. Data are also available on serotonin involvement in cancer cell migration, metastatic processes and as a mediator of angiogenesis. Moreover, the progression of some tumours is accompanied by a dysregulation of the pattern of serotonin receptor expressions. Serum serotonin level was found to be suitable for prognosis evaluation of urothelial carcinoma in the urinary bladder, adenocarcinoma of the prostate and renal cell carcinoma. In some cases, antagonists of serotonin receptors, inhibitors of selective serotonin transporter and of serotonin synthesis have been successfully used to prevent cancer cell growth. This review revaluates serotonin involvement in several types of cancer and at different stages of their progression.

Semaphorin, neuropilin and VEGF expression in glial tumours: SEMA3G, a prognostic marker?

Gliomas are characterised by local infiltration, migration of tumour cells across long distances and sustained angiogenesis; therefore, proteins involved in these processes are most likely important. Such candidates are semaphorins involved in axon guidance and cell migration. In addition, semaphorins regulate tumour progression and angiogenesis. For cell signalling, class-4 semaphorins bind directly to plexins, whereas class-3 semaphorins require additional neuropilin (NRP) receptors that also bind VEGF(165). The anti-angiogenic activity of class-3 semaphorins can be explained by competition with VEGF(165) for NRP binding. In this study, we analysed the expressions of seven semaphorins of class-3, SEMA4D, VEGF and the NRP1 and NRP2 receptors in 38 adult glial tumours. In these tumours, SEMA3B, SEMA3G and NRP2 expressions were related to prolonged survival. In addition, SEMA3D expression was reduced in high-grade as compared with low-grade gliomas. In contrast, VEGF correlated with higher grade and poor survival. Thus, our data suggest a function for a subset of class-3 semaphorins as inhibitors of tumour progression, and the prognostic value of the VEGF/SEMA3 balance in adult gliomas. Moreover, in multivariate analysis, SEMA3G was found to be the only significant prognostic marker.