Combination treatment strategies with a focus on rosiglitazone and adriamycin for insulin resistant liver cancer.

Insulin resistance promotes the occurrence of liver cancer and decreases its chemosensitivity. Rosiglitazone (ROSI), a thiazolidinedione insulin sensitiser, could be used for diabetes with insulin resistance and has been reported to show anticancer effects on human malignant cells. In this paper, we investigated the combination of ROSI and chemotherapeutics on the growth and metastasis of insulin-resistant hepatoma. In vitro assay, ROSI significantly enhanced the inhibitory effects of adriamycin (ADR) on the proliferation, autophagy and migration of insulin-resistant hepatoma HepG2/IR cells via downregulation of EGFR/ERK and AKT/mTOR signalling pathway. In addition, ROSI promoted the apoptosis of HepG2/IR cells induced by ADR. In vivo assay, high fat and glucose diet and streptozotocin (STZ) induced insulin resistance in mice by increasing the body weight, fasting blood glucose (FBG) level, oral glucose tolerance, fasting insulin level and insulin resistance index. Both the growth of mouse liver cancer hepatoma H22 cells and serum FBG level in insulin resistant mice were significantly inhibited by combination of ROSI and ADR. Thus, ROSI and ADR in combination showed a stronger anti-tumour effect in insulin resistant hepatoma cells accompanying with glucose reduction and might represent an effective therapeutic strategy for liver cancer accompanied with insulin resistant diabetes.

DHPAC, a novel microtubule depolymerizing agent, suppresses angiogenesis and vasculogenic mimicry formation of human non-small cell lung cancer.

Angiogenesis and vasculogenic mimicry (VM) are the main causes of tumor metastasis and recurrence. In this study, we investigated the antiangiogenesis and anti-VM formation of a novel microtubule depolymerizing agent, DHPAC, as well as combretastatin A4 (CA4, a combretastatin derivate) in non-small-cell lung cancer (NSCLC), subsequently elucidating the underlying mechanisms. In human umbilical vein endothelial cells (HUVECs), DHPAC could enter cells and inhibit proliferation, migration, and angiogenesis in the presence and absence of conditioned medium from H1299 cells. Interestingly, the inhibition was enhanced under the stimulation of the conditioned medium. Under hypoxia or normoxia, DHPAC suppressed signal transducer and activator of transcription 3 phosphorylation and reduced vascular endothelial growth factor (VEGF) expression and secretion from HUVECs, thus impeding the activation of the downstream signal transduction pathway of VEGF/VEGFR2. However, JNK inhibitors reversed the inhibitory effect of DHPAC on the angiogenesis, suggesting that DHPAC regulated angiogenesis through activating JNK. In H1299 cells, DHPAC could inhibit proliferation, migration, invasion, and the formation of VM. In addition, DHPAC inhibited the phosphorylation of FAK and AKT and decreased the expressions of VEGF, matrix metalloproteinase 2 (MMP2), MMP9 and Laminin 5, suggesting that DHPAC inhibited VM formation via the FAK/AKT signaling pathway. In addition, CA4 showed a similar effect as DHPAC against angiogenesis and VM formation. These new findings support the use of microtubule destabilizing agents as a promising strategy for cancer therapy.

Pantoprazole pretreatment elevates sensitivity to vincristine in drug-resistant oral epidermoid carcinoma in vitro and in vivo.

Resistance to chemotherapeutic agents is a major cause of treatment failure in patients with oral cancer. Proton pump inhibitors (PPIs), essentially H+-K+-ATPase inhibitors which are currently used in the treatment of acid related diseases, have demonstrated promising antitumor and chemo-sensitizing efficacy. The main purpose of the present study was to investigate whether pantoprazole (PPZ, one of PPIs) could increase the sensitivity of chemoresistant oral epidermoid carcinoma cells (KB/V) to vincristine (VCR) and elucidate the underlying action mechanism. Results showed that combination treatment of PPZ and VCR synergistically inhibited the proliferation of KB/V cells in vitro and in vivo. Furthermore, administration of PPZ and VCR not only induce apoptosis and G2/M phase arrest in KB/V cells but also suppress the migration and invasion of KB/V cells. The mechanism underlying synergistic anti-tumor effect of PPZ and VCR was related to the inhibition of the function and expression of P-glycoprotein (P-gp) and the down-regulation of EGFR/MAPK and PI3K/Akt/mTOR signaling pathways in KB/V cells. Additionally, we observed that PPZ treatment induced an increase in lysosomal pH and inhibited the activity of lysosomal enzyme acid phosphatase in KB/V cells, which could functionally reduce the sequestration of VCR in lysosomes and sensitized KB/V cells to VCR. In conclusion, our study demonstrated that PPZ could be included in new combined therapy of human oral cancer (especially on VCR-resistant therapy) together with VCR.

Role and regulation mechanism of Gal-3 in non-small cell lung cancer and its potential clinical therapeutic significance.

Galectin-3 (Gal-3), the only chimeric lectin of the galectin family, affects numerous biological processes and seems to be involved in different physiological and pathophysiological conditions, such as tumor development, invasion and metastasis as well as immune reactions. There is growing evidence to show that Gal-3 participates in the tumorigenesis, invasion and metastasis as well as tumor immunity in non-small cell lung cancer (NSCLC). A better understanding of the molecular mechanisms of Gal-3 involved in NSCLC development is avidly needed as the basis to identify novel therapeutic targets and develop new strategies for the treatment of NSCLC. In this review, we summarized the distribution and expression of Gal-3 in NSCLC which is highly expressed in NSCLC than in normal lung tissues, and the molecular regulation mechanism of Gal-3 in the development of NSCLC, including upregulation of Wnt/ß-catenin pathway and EGFR expression, involvement in Notch signaling pathway, etc. Moreover, Gal-3 promoted the invasion and metastasis of NSCLC through induction of MMPs secretion, cooperation with integrins, and interaction with mucin 1 to promote cancer-endothelial adhesion. Furthermore, Gal-3 binded to Poly-N-acetyl-lactosamine on N-glycans to promote NSCLC metastasis as well as contributing to tumor microenvironment immunosuppression, which might provide potential therapeutic implications for the clinical treatment of NSCLC.

New insights into molecular mechanisms of rosiglitazone in monotherapy or combination therapy against cancers.

Rosiglitazone (ROSI), a member of thiazolidinediones (TZDs) which act as high-affinity agonists of the nuclear receptor peroxisome-proliferator-activated receptor-γ (PPARγ), is clinically used as an antidiabetic drug which could attenuate the insulin resistance associated with obesity, hypertension, and impaired glucose tolerance in humans. However, recent studies reported that ROSI had significant anticancer effects on various human malignant tumor cells. Mounting evidence indicated that ROSI could exert anticancer effects through PPARγ-dependent or PPARγ-independent ways. In this review, we summarized the PPARγ-dependent antitumor activities of ROSI, which included apoptosis induction, inhibition of cell proliferation and cancer metastasis, reversion of multidrug resistance, reduction of immune suppression, autophagy induction, and antiangiogenesis; and the PPARγ-independent antitumor activities of ROSI, which included inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway, inhibition of prostaglandin E2 (PGE2), increasing MAPK phosphatase 1 (MKP-1) expression and regulation of other apoptosis-related cell factors. In addition, we discussed the anti-cancer application of ROSI by monotherapy or combination therapy with present chemotherapeutic drugs in vitro and in vivo. Moreover, we reviewed the phase I cancer clinical trials related to ROSI combined with chemotherapeutics and phase II trials about the anti-cancer effects of ROSI monotherapy and the radiotherapy sensitivity of ROSI.