Lipoic acid a multi-level molecular inhibitor of tumorigenesis.

We discuss how lipoic acid (LA), a natural antioxidant, induces apoptosis and inhibits proliferation, EMT, metastasis and stemness of cancer cells. Furthermore, owing to its ability to reduce chemotherapy-induced side effects and chemoresistance, LA appears to be a promising compound for cancer treatment.

How do glycolytic enzymes favour cancer cell proliferation by nonmetabolic functions?

Cancer cells enhance their glycolysis, producing lactate, even in the presence of oxygen. Glycolysis is a series of ten metabolic reactions catalysed by enzymes whose expression is most often increased in tumour cells. HKII and phosphoglucose isomerase (PGI) have mainly an antiapoptotic effect; PGI and glyceraldehyde-3-phosphate dehydrogenase activate survival pathways (Akt and so on); phosphofructokinase 1 and triose phosphate isomerase participate in cell cycle activation; aldolase promotes epithelial mesenchymal transition; PKM2 enhances various nuclear effects such as transcription, stabilisation and so on. This review outlines the multiple non-glycolytic roles of glycolytic enzymes, which are essential for promoting cancer cells' survival, proliferation, chemoresistance and dissemination.

Cyclin D1 mediates resistance to apoptosis through upregulation of molecular chaperones and consequent redistribution of cell death regulators.

Cyclin D1 is a key regulator of cell proliferation. It also controls other aspects of the cell fate, such as cellular senescence, apoptosis and tumourigenesis. We used B-lymphoid cell lines producing cyclin D1 to investigate the role of this protein in B-cell lymphomas and leukaemias. Constitutive low levels of cyclin D1 had no effect per se on cell proliferation, but conferred resistance to various apoptotic stimuli in B cells. Activation of the pro-apoptotic protein, Bax, was reduced and mitochondrial permeabilization and phosphatidylserine exposure following cytokine withdrawal were delayed in cyclin D1-producing cells. Proteomic analysis showed that the presence of cyclin D1 led to intracellular accumulation of various molecular chaperones. The chaperone, heat shock protein (Hsp)70, bound to both Bax and the mitochondrial apoptosis inducing factor following cytokine withdrawal, and impeded inhibitors of kappaB (IkappaB)-mediated inhibition of nuclear factor-kappaB anti-apoptotic signalling. Impairment of Hsp70 activity--using a pharmacological Hsp inhibitor or transfecting cells with an Hsp70-blocking antibody--restored the cellular response to mitochondrial apoptosis triggering. Thus, constitutive de-novo cyclin D1 production in B cells delays commitment to apoptosis by inducing Hsp70 chaperoning activity on pre- and post-mitochondrial pro-apoptotic factors.

Absence of Bcl-xL down-regulation in response to cisplatin is associated with chemoresistance in ovarian carcinoma cells.

OBJECTIVE: Recurrence and subsequent acquired chemoresistance to platinum-based treatments constitute major hurdles to ovarian carcinoma therapy. Our objective was to examine the involvement of Bcl-xL anti-apoptotic protein in resistance to cisplatin. METHODS: We described the effect of cisplatin on cell cycle and apoptosis induction in sensitive (IGROV1 and OAW42) and resistant (IGROV1-R10 and SKOV3) ovarian carcinoma cell lines. We correlated it with Bcl-xL mRNA and protein expression after exposure to cisplatin. We then used bcl-xS gene transfer to impede Bcl-xL activity. RESULTS: Our study showed that Bcl-xL basal expression was high in both sensitive and resistant cell lines, as well as in all the studied ovarian tumor samples. Thus, Bcl-xL basal expression could not allow to predict sensitivity. Wondering whether variation of Bcl-xL level in response to cisplatin could be a better determinant of sensitivity, we investigated the expression of this protein in the cell lines after treatment. Cisplatin-induced down-regulation of Bcl-xL was strictly associated with apoptosis and absence of recurrence in vitro. Conversely, the maintenance of Bcl-xL expression in response to cisplatin appeared as a sine qua non condition to escape to treatment. To try to sensitize SKOV3 cells by impeding anti-apoptotic activity of Bcl-xL, we transfected bcl-xS gene in these cells. Bcl-xS exogenous expression was only slightly cytotoxic on its own, but highly sensitized SKOV3 resistant cells to cisplatin-induced apoptosis, and delayed recurrence. CONCLUSION: This work thus provides one more argument to put Bcl-xL forward as a pertinent target of inhibition to overcome chemoresistance of epithelial ovarian carcinoma.

The p21(cip1/waf1) cyclin-dependent kinase inhibitor enhances the cytotoxic effect of cisplatin in human ovarian carcinoma cells.

The seriousness of ovarian cancer, which is related to the observed link between recurrency and cell cycle control defect, prompted us to explore the effect of ectopic expression of the cdk inhibitor p21(cip1/waf1) on ovarian carcinoma chemosensitivity. The transfection of p21(cip1/waf1) cDNA into SKOV3 and OVCAR3 cells led to reduction of tumor cell growth, enhanced susceptibility to cisplatin-induced apoptosis, and abolition of recurrency after cisplatin exposure. p21(cip1/waf1) gene transfer allowed a marked reduction of the cisplatin concentration needed to erradicate the tumor cell population. These results suggest exploring the possible use of p21(cip1/waf1) as an adjunctive to conventional chemotherapy.

Acquisition of chemoresistance in a human ovarian carcinoma cell is linked to a defect in cell cycle control.

Chemoresistance is a major concern in cancer erradication; it involves various mechanisms, including defects in the apoptosis program induced by anticancer drugs. In order to further explore the mechanisms underlying the development of chemoresistance in ovarian carcinoma after cisplatin treatment, we established an in vitro model, mimicking a clinical protocol of administration of cisplatin. Therefore, IGROV1 ovarian carcinoma cells were exposed for 2 hr to the drug and allowed to recover for several weeks; this way of exposure was reiterated with escalating doses. We followed changes in cytotoxicity of the drug, cell cycle kinetics and long-term survival of cells after cisplatin treatment, and found that resistance to cisplatin was not associated with altered apoptosis pathway, since both cisplatin sensitive and resistant cells underwent apoptosis in a similar way. Acquisition of resistance to cisplatin was associated with the ability of the treated cells to progress through the cell cycle beyond the G1/S checkpoint; although most cells died by apoptosis, a few surviving cells proliferated and recolonized the cultures. Compared to sensitive cells, the chemoresistant variants were able to override the G1/S checkpoint whatever the dose, and the recurrent cells recolonized the cultures much faster. Analysis of alterations in gene expression suggests that the defect in cell cycle regulation could take place at the level of the cdk inhibitor p21(CIP1/WAF1).