Limocitrin increases cytotoxicity of KHYG-1 cells against K562 cells by modulating MAPK pathway.

Natural killer (NK) cells are gaining popularity in the field of cancer immunotherapy. The present study was designed to investigate the effect of a natural flavonol compound limocitrin in increasing cytotoxicity of a permanent NK leukemia cell line KHYG-1 against an aggressive leukemia cell line K562. The findings revealed that limocitrin increased the expressions of cytolytic molecules perforin, granzymes A and B, and granulysin in KHYG-1 cells by inducing phosphorylation of transcription factor CREB, leading to increased lysis of K562 cells. Mechanistically, limocitrin was found to increase the expressions of t-Bid, cleaved caspase 3, and cleaved PARP to induce K562 cell apoptosis. Moreover, limocitrin reduced the expressions of SET and Ape1 to inhibit DNA repair mechanism, leading to caspase-independent K562 cell death. At the molecular level, limocitrin was found to increase the phosphorylation of ERK, p38, and JNK to increase granzyme B expression in KHYG-1 cells. Taken together, the study indicates that limocitrin increases cytotoxicity of NK cells against a range of cancer cells.

Shuterin Enhances the Cytotoxicity of the Natural Killer Leukemia Cell Line KHYG-1 by Increasing the Expression Levels of Granzyme B and IFN-γ through the MAPK and Ras/Raf Signaling Pathways.

Natural killer (NK) cell therapy is an emerging tool for cancer immunotherapy. NK cells are isolated from peripheral blood, and their number and activity are limited. Therefore, primary NK cells should be expanded substantially, and their proliferation and cytotoxicity must be enhanced. Shuterin is a phytochemical isolated from Ficus thonningii. In this study, we explored the possible capacity of shuterin to enhance the proliferation and activity of KHYG-1 cells (an NK leukemia cell line). Shuterin enhanced the proliferation of KHYG-1 cells and their cytotoxicity to K562 cells. Moreover, this phytochemical induced the expression of granzyme B by promoting the phosphorylated cyclic adenosine monophosphate response element-binding protein (CREB) and mitogen-activated protein kinase (MAPK) signaling pathways. Furthermore, the secretion of interferon (IFN)-γ increased with increasing levels of shuterin in KHYG-1 cells and NK cells obtained from adults with head and neck squamous cell carcinoma. Shuterin appeared to induce IFN-γ secretion by increasing the expression of lectin-like transcript 1 and the phosphorylation of proteins involved in the Ras/Raf pathway. Thus, shuterin represents a promising agent for promoting the proliferation and cytotoxicity of NK cells.

7-Epitaxol Induces Apoptosis and Autophagy in Head and Neck Squamous Cell Carcinoma through Inhibition of the ERK Pathway.

As the main derivative of paclitaxel, 7-Epitaxol is known to a have higher stability and cytotoxicity. However, the anticancer effect of 7-Epitaxol is still unclear. The purpose of this study was to explore the anticancer effects of 7-Epitaxol in squamous cell carcinoma of the head and neck (HNSCC). Our study findings revealed that 7-Epitaxol potently suppressed cell viability in SCC-9 and SCC-47 cells by inducing cell cycle arrest. Flow cytometry and DAPI staining demonstrated that 7-Epitaxol treatment induced cell death, mitochondrial membrane potential and chromatin condensation in OSCC cell lines. The compound regulated the proteins of extrinsic and intrinsic pathways at the highest concentration, and also increased the activation of caspases 3, 8, 9, and PARP in OSCC cell lines. Interestingly, a 7-Epitaxol-mediated induction of LC3-I/II expression and suppression of p62 expression were observed in OSCC cells lines. Furthermore, the MAPK inhibitors indicated that 7-Epitaxol induces apoptosis and autophagy marker proteins (cleaved-PARP and LC3-I/II) by reducing the phosphorylation of ERK1/2. In conclusion, these findings indicate the involvement of 7-Epitaxol in inducing apoptosis and autophagy through ERK1/2 signaling pathway, which identify 7-Epitaxol as a potent cytotoxic agent in HNSCC.

PlatyphyllenoneExerts Anti-Metastatic Effects on Human Oral Cancer Cells by Modulating Cathepsin L Expression, MAPK Pathway and Epithelial-Mesenchymal Transition.

Advanced-stage oral cancers with lymph node metastasis are associated with poor prognosis and a high mortality rate. Although recent advancement in cancer treatment has effectively improved the oral cancer prognosis, the majority of therapeutic interventions are highly expensive and are associated with severe sideeffects. In the present study, we studied the efficacy of a diarylheptanoid derivative, platyphyllenone, in modulating the metastatic potential of human oral cancer cells. Specifically, we treated the human oral cancer cells (FaDu, Ca9-22, and HSC3) with different concentrations of platyphyllenone and measured the cell proliferation, migration, and invasion. The study findings revealed that platyphyllenonesignificantly inhibited the motility, migration, and invasion of human oral cancer cells. Mechanistically, platyphyllenone reduced p38 phosphorylation, decreased ß-catenin and Slug, increased E-cadherin expression, and reduced cathepsin L expression, which collectively led to a reduction in cancer cell migration and invasion. Taken together, our study indicates that platyphyllenone exerts significant anti-metastatic effects on oral cancer cells by modulating cathepsin L expression, the MAPK signaling pathway, and the epithelial-mesenchymal transition process.

Dehydrocrenatidine extracted from Picrasma quassioides induces the apoptosis of nasopharyngeal carcinoma cells through the JNK and ERK signaling pathways.

Nasopharyngeal carcinoma (NPC) is an indicator disease in Asia due to its unique geographical and ethnic distribution. Dehydrocrenatidine (DC) is a ß­carboline alkaloid abundantly present in Picrasma quassioides (D. Don) Benn, a deciduous shrub or small tree native to temperate regions of southern Asia, and ß­carboline alkaloids play anti­inflammatory and antiproliferative roles in various cancers. However, the mechanism and function of DC in human NPC cells remain only partially explored. The present study aimed to examine the cytotoxicity and biochemical role of DC in human NPC cells. The MTT method, cell cycle analysis, DAPI determination, Annexin V/PI double staining, and mitochondrial membrane potential examination were performed to evaluate the effects of DC treatment on human NPC cell lines. In addition, western blotting analysis was used to explore the effect of DC on apoptosis and signaling pathways in related proteins. The analysis results confirmed that DC significantly reduced the viability of NPC cell lines in a dose­ and time­dependent manner and induced apoptosis through internal and external apoptotic pathways (including cell cycle arrest, altered mitochondrial membrane potential, and activated death receptors). Western blot analysis illustrated that DC's effect on related proteins in the mitogen­activated protein kinase pathway can induce apoptosis by enhancing ERK phosphorylation and inhibiting Janus kinase (JNK) phosphorylation. Notably, DC induced apoptosis by affecting the phosphorylation of JNK and ERK, and DC and inhibitors (SP600125 and U0126) in combination restored the overexpression of p­JNK and p­ERK. To date, this is the first study to confirm the apoptosis pathway induced by DC phosphorylation of p­JNK and p­REK in human NPC. On the basis of evidence obtained from this study, DC targeting the inhibition of NPC cell lines may be a promising future strategy for NPC treatment.

Dehydrocrenatidine inhibits head and neck cancer cells invasion and migration by modulating JNK1/2 and ERK1/2 pathway and decreases MMP-2 expression.

Head and neck cancer is associated with poor prognosis because of its highly metastatic nature. For the better management of head and neck cancer patients, it is very important to diagnose the cancer at an early stage, as well as to prevent the rapid spread of cancer either through direct invasion or lymphatic metastasis. In present study, the effect of dehydrocrenatidine, which is a beta-carboline alkaloid found in the medicinal plant Picrasma quassioides, on human head and neck cancer metastasis was investigated. The study results revealed the treatment of FaDu, SCC9, and SCC47 cells with 5, 10, and 20 µM of dehydrocrenatidine significantly decreased the motility, migration, and invasion of head and neck cancer cells. Moreover, the dehydrocrenatidine treatment significantly decreased the expression of MMP-2 and phosphorylation of ERK1/2 and JNK1/2. Additional experiments revealed that the cotreatment of dehydrocrenatidine with either ERK1/2 or JNK1/2 inhibitor caused further reduction in cancer cell motility and migration compared to that in dehydrocrenatidine treatment alone. Moreover, similar trend was observed in case of ERK1/2 and JNK1/2 phosphorylation and MMP-2 expression after the cotreatment. Taken together, the mechanism by which dehydrocrenatidine can decrease the phosphorylation of ERK1/2 and JNK1/2, follow decrease the expression of MMP-2 and inhibits head and neck cancer cells invasion and migration. This present study identifies dehydrocrenatidine as a potent antimetastatic agent that can be used clinically to improve head and neck cancer prognosis.

Pinosylvin inhibits migration and invasion of nasopharyngeal carcinoma cancer cells via regulation of epithelial­mesenchymal transition and inhibition of MMP­2.

Nasopharyngeal carcinoma (NPC) is a tumor located in the nasopharynx with highly invasive and metastatic properties. Metastasis is a primary cause of mortality in patients with NPC. The terpenoid polyphenol pinosylvin is a known functional compound of the Pinus species that exhibits anti­inflammatory effects; however, the effect of pinosylvin on human NPC cell migration and invasion is unclear. The present study aimed to investigate the functional role of pinosylvin in NPC cells (NPC­039, NPC­BM and RPMI 2650). Gap closure and Transwell assay indicated that pinosylvin at increasing concentrations inhibited migration and invasion of NPC­039 and NPC­BM cells. In addition to inhibiting the enzyme activity of MMP­2, pinosylvin also decreased the protein expression levels of MMP­2 and MMP­9. Pinosylvin decreased the expression of vimentin and N­cadherin and significantly increased the expression of zonula occludens­1 and E­cadherin in NPC cells. Additionally, pinosylvin suppressed the invasion and migration ability of NPC­039 and NPC­BM cells by mediating the p38, ERK1/2 and JNK1/2 pathways. The present results revealed that pinosylvin inhibited migration and invasion in NPC cells.

Antimetastatic Effects of Sesamin on Human Head and Neck Squamous Cell Carcinoma through Regulation of Matrix Metalloproteinase-2.

BACKGROUND: Sesamin is a lignin present in sesame oil from the bark of Zanthoxylum spp. Sesamin reportedly has anticarcinogenic potential and exerts anti-inflammatory effects on several tumors. Hypothesis/Purpose: However, the effect of sesamin on metastatic progression in human head and neck squamous carcinoma (HNSCC) remains unknown in vitro and in vivo; hence, we investigated the effect of sesamin on HNSCC cells in vitro. METHODS AND RESULTS: Sesamin-treated human oral cancer cell lines FaDu, HSC-3, and Ca9-22 were subjected to a wound-healing assay. Furthermore, Western blotting was performed to assess the effect of sesamin on the expression levels of matrix metalloproteinase (MMP)-2 and proteins of the MAPK signaling pathway, including p-ERK1/2, P-p38, and p-JNK1/2. In addition, we investigated the association between MMP-2 expression and the MAPK pathway in sesamin-treated oral cancer cells. Sesamin inhibited cell migration and invasion in FaDu, Ca9-22, and HSC-3 cells and suppressed MMP-2 at noncytotoxic concentrations (0 to 40 µM). Furthermore, sesamin significantly reduced p38 MAPK and JNK phosphorylation in a dose-dependent manner in FaDu and HSC-3 cells. CONCLUSIONS: These results indicate that sesamin suppresses the migration and invasion of HNSCC cells by regulating MMP-2 and is thus a potential antimetastatic agent for treating HNSCC.

Luteolin-7-O-Glucoside Inhibits Oral Cancer Cell Migration and Invasion by Regulating Matrix Metalloproteinase-2 Expression and Extracellular Signal-Regulated Kinase Pathway.

Oral squamous cell carcinoma is the sixth most common type of cancer globally, which is associated with high rates of cancer-related deaths. Metastasis to distant organs is the main reason behind worst prognostic outcome of oral cancer. In the present study, we aimed at evaluating the effects of a natural plant flavonoid, luteolin-7-O-glucoside, on oral cancer cell migration and invasion. The study findings showed that in addition to preventing cell proliferation, luteolin-7-O-glucoside caused a significant reduction in oral cancer cell migration and invasion. Mechanistically, luteolin-7-O-glucoside caused a reduction in cancer metastasis by reducing p38 phosphorylation and downregulating matrix metalloproteinase (MMP)-2 expression. Using a p38 inhibitor, SB203580, we proved that luteolin-7-O-glucoside exerts anti-migratory effects by suppressing p38-mediated increased expression of MMP-2. This is the first study to demonstrate the luteolin-7-O-glucoside inhibits cell migration and invasion by regulating MMP-2 expression and extracellular signal-regulated kinase pathway in human oral cancer cell. The study identifies luteolin-7-O-glucoside as a potential anti-cancer candidate that can be utilized clinically for improving oral cancer prognosis.

Pinosylvin reduced migration and invasion of oral cancer carcinoma by regulating matrix metalloproteinase-2 expression and extracellular signal-regulated kinase pathway.

BACKGROUND: Pinosylvin possesses several biological properties, including anti-inflammatory, antitumor, and antioxidant characteristics. However, the effects of pinosylvin on the migration and invasion of human oral cancer cells and the underlying mechanisms remain unclear. HYPOTHESIS/PURPOSE: In this research, we investigated the outcome of different concentrations of pinosylvin (0-80 µM) on the metastatic and invasive abilities of SAS, SCC-9, and HSC-3 cells. METHODS AND RESULTS: Western blotting assay and Gelatin zymography assay indicated that pinosylvin inhibited the enzymatic activity of matrix metalloproteinase-2 (MMP-2) and reduced its protein level but increased the expression of tissue inhibitor of metalloproteinase-2 (TIMP-2). Additionally, the wound healing assay and Transwell method showed that pinosylvin reduced the migration of SAS, SCC-9 and HSC-3 oral cancer cells. Besides, pinosylvin decreased the phosphorylation of ERK1/2 protein experssion in both SAS and SCC-9 cells. CONCLUSION: These results indicate that pinosylvin is a potential anticancer agent for preventing oral cancer metastasis.

Celastrol, a plant-derived triterpene, induces cisplatin-resistance nasopharyngeal carcinoma cancer cell apoptosis though ERK1/2 and p38 MAPK signaling pathway.

BACKGROUND: Developing resistance to chemotherapeutic drugs has become a major problem in the management of nasopharyngeal carcinoma (NPC). To overcome this issue, use of natural plant products as chemosensitizers is gaining importance at a fast pace. HYPOTHESIS/PURPOSE: The present study was designed to evaluate the cytotoxic effect and mode of action of a natural pentacyclic triterpenoid, celastrol, on cisplatin-resistant NPC cells. RESULTS: Study results revealed that celastrol treatment significantly reduced the viability of NPC cells in dose and time dependent manners, as compared to untreated control cells. The cytotoxic effect of celastrol was mediated by cell cycle arrest at G2/M phase and induction of intrinsic and extrinsic apoptotic pathways. With further analysis, we observed that celastrol-induced activation of caspases was accompanied by increased phosphorylation of MAPK pathway proteins, p38, ERK1/2. CONCLUSION: Taken together, our observation provides a novel insight on use of a natural plant product, celastrol, in the management of chemoresistant NPC.

Coronarin D induces human oral cancer cell apoptosis though upregulate JNK1/2 signaling pathway.

The incidence of oral cancer is increasing all over the world, with rates particularly high in Southeast Asian countries, such as Taiwan. Coronarin D (CD) has been confirmed to have anti-inflammatory, anti-bacterial effects, and anti-apoptotic effects in human hepatocellular carcinoma and nasopharyngeal carcinoma. The purpose of this study is to explore whether CD has a suppression effect on oral cancer cells and the mechanisms involved. The results of our study revealed the significantly decreased cancer cell viability and increased activation of apoptosis via increased loss of mitochondrial membrane potential, increased death receptors, leading to the activation of caspase-8, -9, -3. Moreover, the rate of apoptosis of cells treated with CD plus JNK inhibitors was decreased compared to CD-treated cells. This is the first study to demonstrate that CD induces apoptosis in human oral cancer cells and can be expected to be a promising anticancer agent for oral cancer treatment.

Erianin induces cell apoptosis through ERK pathway in human nasopharyngeal carcinoma.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is one of the most common cancers in areas of Southeast Asia, such as Taiwan, and North Africa. The treatments of NPC, including radiotherapy and chemotherapy, were effective, but they also caused some severe side effects. Erianin, a natural product derived from Dendrobium, was proved to have anti-cancer effect in hepatoma, melanoma, non-small-cell lung carcinoma, myelogenous leukemia, breast cancer, and osteosarcoma. HYPOTHESIS/PURPOSE: According to previous research, we hypothesized that erianin inhibits cancer cell growth through apoptotic mechanisms. This study aimed to determine whether Erianin has an anti-NPC effect and what mechanisms were involved. METHODS AND RESULTS: The result showed that erianin significantly increased activation of apoptosis in NPC cell lines (NPC-039 and NPC-BM) and arrest the cell cycle obviously through mitochondrial membrane alternation, death receptors activation, and caspase-3, -8, -9 activation. Phosphorylated ERK1/2 was also decreased in erianin-treated NPC cell with dose-dependent manner, and the result was thought to promote apoptosis. Furthermore, the increased rate of apoptotic cells with erianin plus it's inhibitors (U) was also revealed in this study. CONCLUSION: In conclusion, this is the first research to identify the anti-NPC effect of erianin via the apoptosis mechanism. Erianin was a promising natural agent against nasopharyngeal carcinoma.

Is definitive concurrent chemoradiotherapy effective for locally advanced head and neck cancer in the elderly aged ≥ 75 years: A single-institute, retrospective, cohort study.

BACKGROUND: Definitive chemoradiotherapy (CRT) is the standard treatment for locally advanced head and neck cancer (HNC). However, for very elderly patients, the comparison of benefit/risk between definitive radiotherapy (RT) with and without systemic chemotherapy was equivocal. PATIENTS AND METHODS: The study was a single-institute, retrospective, cohort study. Seventy patients aged ≥75 years who had a locally advanced HNC were enrolled. The patients were divided into those with CRT and those with RT alone. Survival, compliance/adverse events and independent prognostic factors were analyzed. RESULTS: For baseline characteristics, the patients who received RT alone had worse performance status, comorbidity score and neutrophil-to-lymphocyte ratio. However, during definitive therapy, the CRT group had more adverse events such as neutropenia, febrile neutropenia and thrombocytopenia. There were no significant differences in disease-specific survival (DSS) and overall survival (OS) (P = 0.864 and 0.788, respectively). As to OS, several independent prognostic factors were identified. Performance status (hazard ratio [HR], 2.312; confidence interval [CI], 1.176-4.546; P = 0.015), clinical T staging (HR, 2.240; 95% CI, 1.021-4.913; P = 0.004) and total RT dose (HR, 2.555; 95% CI, 1.246-5.238; P = 0.010) were independent prognostic factors of OS. CONCLUSIONS: Definitive RT with or without systemic chemotherapy did not significantly influence DSS and OS for very elderly patients. Therefore, for elderly patients aged ≥ 75 years who have HNC, conservative RT might be sufficient for treatment purposes.

Functional FGFR4 Gly388Arg polymorphism contributes to oral squamous cell carcinoma susceptibility.

Aberrations of the fibroblast growth factor receptor 4 (FGFR4) genomic region include amplification of FGFR4, activation of FGFR4 kinase domain mutations, and overexpression of FGFR4, which lead to sustained cell proliferation and contribute to tumor development. However, the association between FGFR4 single-nucleotide polymorphisms (SNPs) and risk of oral squamous cell carcinoma (OSCC) remains to be determined. We investigated the relationships between FGFR4 genetic polymorphisms, OSCC development and clinicopathological variables. We recruited a total of 955 patients with OSCC and 1191 controls. Four SNPs of FGFR4 (rs2011077, rs351855, rs7708357, and rs1966265) were examined using real-time polymerase chain reaction. We found that with the rs351855 GA genotype and a combination of the GA and AA genotypes exhibited a 1.431-fold (95% CI: 1.092-1.876) and 1.335-fold (95% CI: 1.033-1.725) higher risk of OSCC. However, patients with OSCC with a homozygous A/A genotype of FGFR4 rs351855 polymorphism had a lower risk of advanced stage OSCC (P = 0.0252). Furthermore, the patients with the FGFR4 rs351855/rs1966265 A-A haplotype had a 2.890-fold (95% confidence interval [CI]: 2.257-3.700) higher risk of OSCC than the controls. Betel quid chewers with the A-A haplotype had a considerably higher risk (95% CI: 16.159-26.937) of OSCC than did betel quid nonchewers with other haplotypes. Moreover, an additional integrated in silico analysis proposed that rs351855 G allele variant to the A allele exhibited a relatively low energy of the transmembrane region. In conclusion, our results suggest that the FGFR4 rs351855 may play a role in susceptibility for OSCC development.

Polyphyllin G induces apoptosis and autophagy cell death in human oral cancer cells.

BACKGROUND: Polyphyllin G (also called polyphyllin VII), extract from rhizomes of Paris yunnanensis Franch, has been shown to have strong anticancer activities in a wide variety of human cancer cell lines. However, the underlying influences of autophagy in human oral squamous cell carcinoma (OSCC) remain unclear. METHODS: In this study, the roles of apoptosis and autophagy in polyphyllin G-induced death in human oral cancer cells were investigated. Moreover, the molecular mechanism of the anticancer effects of polyphyllin G in human oral cancer cells was investigated. RESULTS: The results revealed that polyphyllin G significantly inhibited cell proliferation in human oral cancer cells; it dose-dependently induced apoptosis in SAS and OECM-1 cells through caspase-3, -8, and -9 activation and poly (ADP-ribose) polymerase cleavage. In addition, changes were observed in Bcl-2 and proapoptosis-related protein expression in different human oral cancer cell lines. The expression of both LC3-II and beclin-1 was markedly increased, suggesting the induction of autophagy in polyphyllin G-treated oral cells. To further clarify whether polyphyllin G-induced apoptosis and autophagy depended on Akt/extracellular signal-regulated kinases (ERK)/c-Jun N-terminal kinases (JNK)/p38 mitogen-activated protein kinases (MAPK) signaling pathways, the cells were cotreated with inhibitors. The results demonstrated polyphyllin G-induced apoptosis in oral cells through the activation of ERK, Akt, p38 MAPK, and JNK, whereas ERK and JNK accounted for polyphyllin G-induced autophagy. CONCLUSION: This study is the first to demonstrate apoptosis and autophagy during polyphyllin G-induced cell death in human oral cancer cell lines. These results suggest that polyphyllin G is a promising candidate for developing antitumor drugs targeting human oral squamous cell carcinoma.

Polyphyllin G induce apoptosis and autophagy in human nasopharyngeal cancer cells by modulation of AKT and mitogen-activated protein kinase pathways in vitro and in vivo.

Polyphyllin G (also call polyphyllin VII), extract from rhizomes of Paris yunnanensis Franch, has been demonstrated to have strong anticancer activities in a wide variety of human cancer cell lines. Previous studies found that Polyphyllin G induced apoptotic cell death in human hepatoblastoma cancer and lung cancer cells. However, the underlying mechanisms of autophagy in human nasopharyngeal carcinoma (NPC) remain unclear. In this study, Polyphyllin G can potently induced apoptosis dependent on the activations of caspase-8, -3, and -9 and the changes of Bcl-2, Bcl-xL and Bax protein expression in different human NPC cell lines (HONE-1 and NPC-039). The amount of both LC3-II and Beclin-1 was intriguingly increased suggest that autophagy was induced in Polyphyllin G-treated NPC cells. To further clarify whether Polyphyllin G-induced apoptosis and autophagy depended on AKT/ERK/JNK/p38 MAPK signaling pathways, cells were combined treated with AKT inhibitor (LY294002), ERK1/2 inhibitor (U0126), p38 MAPK inhibitor (SB203580), or JNK inhibitor (SP600125). These results demonstrated that Polyphyllin G induced apoptosis in NPC cells through activation of ERK, while AKT, p38 MAPK and JNK were responsible for Polyphyllin G-induced autophagy. Finally, an administration of Polyphyllin G effectively suppressed the tumor growth in the NPC carcinoma xenograft model in vivo. In conclusion, our results reveal that Polyphyllin G inhibits cell viability and induces apoptosis and autophagy in NPC cancer cells, suggesting that Polyphyllin G is an attractive candidate for tumor therapies. Polyphyllin G may promise candidate for development of antitumor drugs targeting nasopharyngeal carcinoma.

Colon cancer mesenchymal stem cells modulate the tumorigenicity of colon cancer through interleukin 6.

Multipotent mesenchymal stem cells (MSCs) have been isolated from several tumors and are implicated to play critical roles to increase malignant cell growth, invasion and metastasis. Here, we show that the MSC-like cells were isolated from human colon cancer tissues. These isolated hCC-MSCs (human colon cancer-derived mesenchymal stem cells) shared similar characteristic features with bone marrow-derived MSCs, which include cell morphology, surface antigens and specific gene expression. Additionally, the hCC-MSCs could differentiate into osteocytes or adipocytes under appropriate culture conditions. The conditioned medium collected from the cultured hCC-MSCs was shown to enhance the migration and invasive activity of HCT-116 colon cancer cells in vitro. Besides, transplantation of HCT-116 cells along with hCC-MSCs in nude mice increased the tumor growth and metastasis. Further study revealed that IL-6 present in the hCC-MSC-conditioned medium sufficiently induced the levels of Notch-1 and CD44 in HCT-116 and HT-29 cells, which contribute to enhance tumorigenic activity of HCT-116 and HT-29 cells. By using immunohistochemical staining, the intense co-expression of IL-6, Notch-1 and CD44 was predominantly detected in human colon cancer tissues. Taken together, our findings suggest the importance of the IL-6/Notch-1/CD44 signaling axis in the interaction between hCC-MSCs and colon cancer cells.

Chemotherapy with modified docetaxel, cisplatin, and 5-fluorouracil in patients with metastatic head and neck cancer.

INTRODUCTION: This retrospective study evaluates the efficacy of palliative chemotherapy with a modified docetaxel, cisplatin, 5-fluorouracil (5-FU; "TPF" regimen) regimen (mTPF; reduced doses of docetaxel, cisplatin, and 5-FU with reduction of intravenous 5-FU from 4 days to 2 days) in Asian patients with recurrent and metastatic squamous cell carcinoma of head and neck (HNSCC) after surgery and adjuvant chemoradiation. METHODS: The mTPF regimen was used in this study. Fifty-five patients (from January 2007 to October 2009) received docetaxel on day 1, followed by cisplatin and 5-FU administered continuous infusion on day 2 for another 48 hours every 3 weeks for three to six cycles. RESULTS: The disease control rate was 81%. The overall response rate was 56%. Five patients achieved complete remission; 26 patients had partial remission; 14 patients had stable disease. Ten patients had disease progression. The metastatic sites that responded well to mTPF regimen (either complete or partial remission) were: neck lymph node, lung, liver, and skin. The median follow-up was 15 months (range 1-28 months). The median overall survival was 10 months (range 2-28 months). The common nonhematological toxicity was alopecia and the most common hematological adverse event was neutropenia. Thirty-one patients (56%) had grade 3-4 neutropenia. CONCLUSION: The mTPF chemotherapy regimen is efficacious for the palliative treatment of recurrent and metastatic HNSCC in Asian patients.