PPARgamma ligand (thiazolidinedione) induces growth arrest and differentiation markers of human pancreatic cancer cells

The aim of this study was to examine whether a specific PPARgamma ligand can inhibit the growth of human pancreatic cancer cells through induction of terminal differentiation. PPARgamma was expressed in five human pancreatic cancer cell lines: Capan-1, AsPC-1, BxPC-3, PANC-1, and MIA PaCa-2. Treatment of these cells with a specific PPARgamma ligand, thiazolidinedione (TZD), resulted in inhibition of both cellular and clonogenic growth, and G1 cell cycle arrest. Finally, thiazolidinedione treatment resulted in induction of p21WAF-1 and increased expression of differentiation markers. These results suggest that thiazolidinedione treatment inhibits growth and induces cellular differentiation in pancreatic cancer cells and thereby reduces their development in favor of differentiated and stable cell phenotype.     

Carcinogenic potential of alizarin and rubiadin, components of madder color, in a rat medium-term multi-organ bioassay

Madder color (MC), a food coloring extracted from roots of Rubia tinctorum L., has been proven to exert carcinogenicity in the rat kidney and liver. Furthermore, it induces DNA adducts in the kidney, liver, and colon. MC is in fact composed of anthraquinones such as lucidin-3- O -primeveroside and alizarin. To clarify which of these might be responsible for the carcinogenicity, a rat medium-term multi-organ carcinogenesis bioassay was performed focusing on the kidney, liver, and colon. Male 6-week-old F344 rats after receiving five different carcinogens were fed a diet containing either 0.008% or 0.04% of alizarin or rubiadin, a metabolite of lucidin-3- O -primeveroside, for 23 weeks. Treatment with 0.04% rubiadin significantly increased atypical renal tubules/hyperplasias and induced renal cell adenomas and carcinomas. Renal cell tumors were also increased with 0.04% alizarin, although at lower incidence than with rubiadin. In addition, glutathione S -transferase placental form-positive liver cell foci and large intestinal dysplasias were significantly increased with 0.04% rubiadin. These results indicate that both rubiadin and alizarin can increase renal preneoplastic lesions, the potential of the latter being weaker. Rubiadin may also target the liver and large intestine, suggesting a major role in madder color-induced carcinogenicity. ( Cancer Sci 2009; 100: 2261–2267)     

Primary osteosarcoma of ovary

Primary osteosarcoma originating from the ovary is an exceedingly rare, highly malignant tumor. Only a few cases have been reported in the past few decades. We describe a 50-year-old postmenopausal woman who presented with a large abdominal mass. The clinical diagnosis was malignant ovarian cancer. Her disease was aggressive; she had no response to systemic chemotherapy and died within 1 month of presentation. A definitive diagnosis of primary ovarian osteosarcoma was made by histopathological examination of autopsy specimens. Although rare, primary ovarian osteosarcoma should be considered in the differential diagnosis of a large, rapidly progressing pelvic mass in a postmenopausal woman. Early diagnosis provides hope of a complete surgical resection, which is currently the only promising treatment.     

HTLV-1-associated Myelopathy/Tropical Spastic Paraparesis-like Rats by Intravenous Injection of HTLV-1-producing Rabbit or Human T-Cell Line into Adult WKA Rats

We intravenously injected Ra-1 cells or MT-2 cells into female adult WKA rats. Spastic paraparesis mainly in the hind-limbs was observed in 1 out of 2 Ra-1 cell-injected WKA rats and in 3 out of 8 MT-2 cell-injected WKA rats 20 27 months after injection. The main neuropathological finding was symmetrical white matter degeneration with mononuclear cell infiltration of the spinal cord, similar to that of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients, and degeneration of nerve roots and peripheral nerves. Antibodies against HTLV-1 antigens were detected in plasma and cerebrospinal fluid from these HAM/TSP-like rats. HTLV-1 provirus was detected from the peripheral blood mononuclear cells of one of these rats 20 months after injection. Interestingly, spastic paraparesis was not observed in F344 rats.     

Genetic Changes and Histopathological Grades in Human Hepatocellular Carcinomas

Loss of heterozygosity (LOH) on chromosomes 1p, 4q, 5q, 8p, 13q, 16q, 17p, and 22q, and mutation of the p53 gene were simultaneously analyzed in 63 hepatocellular carcinomas (HCCs) with distinct histopathological grades, 80% of the tumors being from patients who had been exposed to hepatitis B virus (HBV) or hepatitis C virus (HCV). The frequencies of LOH on 8 chromosomes were 0–25% in 10 well differentiated HCCs, LOH being observed on 4q, 5q and 17p, 21–53% in 26 moderately differentiated HCCs, LOH on 8p and 17p being high, and 29–75% in 27 poorly differentiated HCCs, LOH on 17p, 4q and 8p heing the most frequent. p53 gene mutation was detected in moderately and poorly differentiated HCCs at 15% and 52%, respectively, but not at all in well differentiated HCCs. Of the mutations detected, 42% were transition mutation and only 5% were CpG transition, in contrast to the high frequencies of these types of mutations in colon tumors (78% and 54%, respectively). LOH on every chromosome and p53 mutation were more frequent in more advanced tumors, and accumulation of genetic changes increased with increase of the histopathological grade. Frequency of genetic changes in HCCs from HBV-positive patients was comparable to that from HCV-positive patients. The present results suggest that accumulation of genetic changes in multiple tumor suppressor genes, especially LOH on 17p, 4q and 8p, and mutation in p53 gene, are involved in the progression of liver cancer, and LOH on 17p and 4q precedes other genetic changes. Differences in the direction of p53 mutation between HCC and colon carcinoma suggest that liver carcinogens are distinct from colon carcinogens. Furthermore, mechanisms affecting the frequency of LOH in HCCs in HBV-infected patients may be similar to those in HCV-infected patients.     

Loss of MKK4 expression in ovarian cancer: A potential role for the epithelial to mesenchymal transition

In the current study, we investigated the mechanism relating downregulation of mitogen‐activated protein kinase kinase 4 (MKK4) expression to development of ovarian cancer. Over‐expression of the MKK4 gene in TOV‐21 G cells, a line with homozygous deletion of MKK4, resulted in morphologic changes in which cells growing in a scattered, fibroblast‐like pattern formed tightly packed colonies. Based on a wound healing assay and a Matrigel invasion assay, we determined that both motility and invasiveness of MKK4‐transfected TOV‐21G cells were significantly reduced compared to control vector‐transfected cells. To confirm that MKK4 expression related to tumor invasion resulted from an epithelial to mesenchymal transition (EMT)‐like morphological change, we used 2 independent but complementary approaches. MKK4 gene knockdown in MDAH 2774 cells over‐expressing MKK4 increased invasion activity. Additionally, engineered expression of MKK4 in SKOV3 cells, a line with low endogenous MKK4 expression, produced a phenotype similar to that of TOVG‐21G. Interestingly, we found that MKK4 upregulation caused downregulation of phosphorylated NF‐κB and Twist, as well as upregulation of E‐cadherin, in TOVG‐21G and SKOV3 cells. Reciprocal results were obtained in MDAH 2774 cells with MKK4 knockdown. Our results suggest that MKK4 downregulation causes increased phosphorylation NF‐κB. This promotes Twist over‐expression, resulting in E‐cadherin downregulation that induces EMT in ovarian cancer.     

A FGFR2 inhibitor, Ki23057, enhances the chemosensitivity of drug-resistant gastric cancer cells

Aim

The aim of this study was to clarify the ability of a FGFR2 inhibitor, Ki23057, to enhance the chemosensitivity of drug-resistant gastric cancer cell lines when used in combination with chemotherapeutic drugs.

Materials and methods

Five cancer cell lines resistant to irinotecan (SN38), paclitaxel (PTX), etoposide (VP16), oxaliplatin (OXA), and gemcitabine (GEM) were respectively established from a parent gastric cancer cell line, OCUM-2M, and were named OCUM-2M/SN38, OCUM-2M/PTX, OCUM-2M/VP16, OCUM-2M/OXA, and OCUM-2M/GEM. The effects of the combination of Ki23057 with anticancer drugs on proliferation, apoptosis, and mRNA expression were examined.

Results

Ki23057 significantly decreased the IC₅₀ values of OCUM-2M/SN38, OCUM-2M/PTX, and OCUM-2M/VP16, but not those of OCUM-2M/OXA and OCUM-2M/GEM. Ki23057 significantly enhanced the apoptosis rates induced by chemotherapeutic drugs in both the drug-resistant cell lines and the parental cell line. Ki23057 decreased the ERCC1 expression level in OCUM-2M/SN38, OCUM-2M/PTX, and OCUM-2M/VP16. Ki23057 increased the p53 expression level in OCUM-2M/SN38 and OCUM-2M/PTX, but not in OCUM-2M/VP16.

Conclusion

The FGFR2 inhibitor Ki23057 might be therapeutically promising for treating drug-resistant gastric cancer cells, especially when used in combination with SN38, PTX, or VP16. The apoptosis process might be the main mechanism underlying the synergistic effect of these combinations. The ERCC1 and p53 genes may play an integral role in the synergism between Ki23057 and chemotherapeutic agents in drug-resistant cell lines.