Su-Yu Chien

The Potential Utility of Curcumin in the Treatment of HER-2-Overexpressed Breast Cancer: An In Vitro and In Vivo Comparison Study with Herceptin

HER-2 is an important oncoprotein overexpressed in about 15–25% of breast cancers. We hypothesized that the ability of curcumin to downregulate HER-2 oncoprotein and inhibit the signal transduction pathway of PI3K/Akt, MAPK, and NF-κB activation may be important in the treatment of HER-2-overexpressed breast cancer. To examine the effect of curcumin on breast cancer cells, MCF-7, MDA-MB-231, MCF-10A, BT-474, and SK-BR-3-hr (a herceptin resistant strain from SK-BR-3) cells were used for in vitro analysis. The in vivo effect of curcumin on HER-2-overexpressed breast cancer was investigated with the HER-2-overexpressed BT-474 xenograft model. Cell growth, cell cycle change, the antimobility effect, signal transduction, and xenograft volume analysis between groups treated with herceptin and/or curcumin were tested. Curcumin decreased the cell growth of various breast cancer cell lines (MCF-7, MDA-MB-231, MCF-10A, BT-474, and SK-BR-3-hr). In Western blot analysis, the phosphorylation of Akt, MAPK, and expression of NF-κB were reduced in BT-474 cells, but not in SK-BR-3-hr cells, after treatment with herceptin. When treated with curcumin, the HER-2 oncoprotein, phosphorylation of Akt, MAPK and expression of NF-κB were decreased in both BT-474 and SK-BR-3-hr cells. In the BT-474 xenograft model, though not as much as herceptin, curcumin did effectively decrease the tumor size. The combination of curcumin with herceptin was not better than herceptin alone; however, the combination of taxol and curcumin had an antitumor effect comparable with taxol and herceptin. The results suggested that curcumin has potential as a treatment for HER-2-overexpressed breast cancer.

Capsaicin may induce breast cancer cell death through apoptosis-inducing factor involving mitochondrial dysfunction

The majority of breast cancer patients are resistant to chemotherapy or radiotherapy due to the down-regulation or lack of caspase-3 expression. Capsaicin was found to inhibit cancer cell growth in caspase-3-deficient human breast cancer cells. This study aimed to investigate the growth-inhibitive effect of capsaicin and its mechanisms in human breast cancer cell lines, MCF-7 and BT-20. The results showed that cell viability decreased in a dose-dependent manner in both the caspase-3-deficient and non-deficient cells through inducing cell apoptosis and arresting the cell cycle in the S phase. Capsaicin significantly decreased mitochondria membrane potential, induced the cleavage of PARP-1, and decreased procaspase-7 expression in both cells. Apoptosis-inducing factor (AIF) was distinctly released from mitochondria and translocated into the cytoplasm and nucleus in MCF-7 cells (52.9%), but not in BT-20 cells (2%) after treatment with 200 μM of capsaicin for 24 hours. Capsaicin inhibited breast cancer cell growth through inducing cell apoptosis and cell cycle arrest in the S phase. This apoptotic effect could be induced through the mitochondrial pathway, and PARP-1 subsequently cleaved by activation of caspase-7. The application of capsaicin in clinical therapy could be useful for breast cancer patients.

Tanshinone IIA inhibits human hepatocellular carcinoma J5 cell growth by increasing Bax and caspase 3 and decreasing CD31 expression in vivo

Tanshinone IIA (Tan-IIA) decreases the viability of human hepatocellular carcinoma (HCC) cells through the induction of apoptosis in vitro. However, there are no reports that Tan-IIA is capable of inhibiting J5 HCC cell growth in vivo. In this study, J5 cells were implanted directly into nude SCID mice which were divided randomly into four groups to be treated with vehicle, Tan-IIA (30 mg/-kg of body weight, Q.week days 3 and 5), 5-FU (30 mg/-kg of body weight, Q.week day 1) or Tan-IIA (30 mg/-kg of body weight, Q.week days 3 and 5) plus 5-FU (30 mg/-kg of body weight, Q.week day 1). Each agent was injected intraperitoneally, with treatment starting 4 weeks after inoculation with J5 cells. Treatment with Tan-IIA 30 mg/-kg or with 30 mg/-kg of 5‑FU resulted in a reduction in tumor size and weight compared with the control group. The protein expression of Bax and caspase-3 in the J5 xenograft tumors treated with Tan-IIA 30 mg/-kg or with 30 mg/kg of 5-FU was upregulated, whereas that of CD31 was downregulated compared with the control group. These findings indicate that Tan-IIA may inhibit tumor growth in a J5 xenograft animal model by increasing Bax and caspase 3 and decreasing CD31 expression in vivo.

SIRT1 suppresses breast cancer growth through downregulation of the Bcl-2 protein.

Silent mating-type information regulation 2 homologue 1 (SIRT1), a member of the class III histone deacetylase (HDAC) family, is the mammalian ortholog of yeast Sir2. It has been reported to play a key role in a variety of physiological processes such as genomic stability, metabolism, neurogenesis and cell survival. The deacetylase function of SIRT1 has been suggested to play a role in prolonging the life of mammals. However, the suggested functions of SIRT1 as a potential tumor promoter have been challenged by observations of their respective downregulation and upregulation in various types of cancer. Breast cancer patients were included in the present study between 2007 and 2008. Their tumor tissues and paired normal breast tissues were collected and used for evaluation of the expression levels of SIRT1 and Ki67. The effects of SIRT1 on human breast cancer cell lines were also investigated. Immunohistochemistry showed that there is a high correlation between SIRT1 and Ki67 expression. Following treatment with sirtinol (inhibitor of SIRT1), the expression of the pro-survival protein Bcl-2 was markedly decreased in both MCF-7 and MDA-MB-231 cell lines, particularly in MDA-MB-231. Results of the present study revealed that inhibition of SIRT1 activity may be a promising chemotherapeutic strategy against breast cancer.

Tanshinone IIA inhibits human breast cancer MDA-MB-231 cells by decreasing LC3-II, Erb-B2 and NF-κBp65

The ability of tanshinone IIA (Tan-IIA) to inhibit the proliferation of human breast cancer cell lines in vitro and in vivo is well documented. However, the molecular mechanisms have not been fully elucidated. In the present study, MDA-MB-231 cells were treated with different concentrations of Tan-IIA for 48 h, followed by protein extraction for western blotting. For an in vivo study, MDA-MB-231 cells were implanted directly into female SCID mice which were divided randomly into three groups to be treated with vehicle, Tan-IIA (20 mg/kg) and Tan-IIA (60 mg/kg) every other day orally, with treatment starting 4 weeks after inoculation with the MDA-MB-231 cells. The results showed that Tan-IIA inhibited the proliferation of MDA-MB-231 cells and decreased the protein expression of LC3-II and Erb-B2 in vitro. Treatment with Tan-IIA (20 or 60 mg/kg) for 90 days resulted in a reduction in tumor size and weight compared to the control group. The protein expression of NF-κBp65 was reduced, while caspase-3 was up-regulated compared to the control group. These findings indicate that Tan-IIA inhibits tumor growth in a MDA-MB-231 xenograft animal model. One of the molecular mechanisms may be through a decrease in NF-κBp65 and an increase in caspase-3 expression.

Effect of Supplementation of Tanshinone IIA and Sodium Tanshinone IIA Sulfonate on the Anticancer Effect of Epirubicin: An In Vitro Study

Tanshinone IIA (Tan IIA) and sodium tanshinone IIA sulfonate (STS) were found to have protective effects on cardiomyocyte against adriamycin-induced damage and may be used clinically. It is unclear whether the supplementation of STS or Tan IIA would affect the anticancer activity of anthracycline. To evaluate the effect of Tan IIA or STS on the anticancer of epirubicin, the cell viability, apoptosis, Akt expression, and uptake of epirubicin after supplementation of Tan IIA or STS in the epirubicin-treated BT-20 cells were measured and compared. Tan IIA inhibited BT-20 cell growth and induced apoptosis in a time- and dose-dependent manner. When Tan IIA was used with epirubicin, an increase of BT-20 cells apoptosis was accompanied by the decreasing phosphorylation of Akt. STS had no effect on the cell viability of BT-20 cells. However, when used with epirubicin, STS decreased the epirubicin-induced cytotoxicity and apoptosis in BT-20 cells. The antagonistic effect of STS on epirubicin-induced cytotoxicity in BT-20 cells occurred concomitantly with the reduced epirubicin uptake and the increased phosphorylation of Akt. STS decreased the uptake of epirubicin in BT-20 cells and blocked epirubicin-induced apoptosis through activation of Akt.

Pure mucinous carcinoma of the breast: clinicopathologic characteristics and long-term outcome among Taiwanese women

BackgroundPure mucinous carcinoma (MC) is found in about 3.5% of all newly diagnosed breast cancer patients in Taiwan. MC is a relatively rare malignancy of breast cancer, and its nature, behaviors, treatment pattern and long-term follow-up are not well understood. The study aimed to investigate the incidence rate, treatment patterns, and prognostic factors of MC of the breast and the clinical long-term outcomes compared with infiltrating ductal carcinoma not otherwise specified (IDC) in the middle and south Taiwanese women.MethodsData from 93 patients with breast MC were retrospectively reviewed and the clinicopathologic characteristics and survival status were compared with those of 2,674 patients with IDC.ResultsThe expression of hormonal receptor was higher in MC than those in IDC (P <0.001). MC also demonstrated lower Her2/neu gene over-expression (P = 0.023), less axillary lymph node involvement (P <0.0001), lymphovascular invasion (P <0.0001) and higher 10-year overall survival rate (P = 0.042), when compared with those of IDC.ConclusionOur data confirm the less aggressive behavior of MC compared to IDC. MC showed favorable clinicopathologic characteristics in tumor grade, hormone receptor status and lymph node involvement in the middle and south Taiwanese women.

Sann-Joong-Kuey-Jian-Tang decreases the protein expression of Mcl‑1 and TCTP and increases that of TNF-α and Bax in BxPC‑3 pancreatic carcinoma cells.

Sann-Joong-Kuey-Jian-Tang (SJKJT), a traditional Chinese medicinal prescription, has been used for the treatment of lymphadenopathy and solid tumors, and has shown therapeutic potential in several human malignant tumor cell lines. However, the efficacy and molecular mechanisms of action of SJKJT in human pancreatic cancer have not yet been elucidated. In the present study, we evaluated the cytotoxic effects of SJKJT on BxPC-3 human pancreatic carcinoma cells by MTT assay. The protein expression levels of myeloid cell leukemia 1 protein (Mcl-1), translationally controlled tumor protein (TCTP), tumor necrosis factor-α (TNF‑α), caspase-8, caspase-3, Bax and Bcl-2 family in the BxPC-3 cells were measured by western blot analysis. The cell cycle was analyzed by flow cytometry. The protein expression of caspase-3 was also detected by immunocytochemistry (ICC). The results revealed that SJKJT inhibited the proliferation of BxPC-3 cells in a time- and dose-dependent manner. The protein expression levels of TNF-α, caspase-8, caspase-3 and Bax increased in the BxPC-3 cells treated with SJKJT; however, the levels of Mcl-1, TCTP and Bcl-xL decreased. The results also demonstrated that SJKJT increased the percentage of BxPC-3 cells in the sub-G1 phase. In addition, ICC staining indicated that the protein expression of caspase-3 was upregulated in the BxPC-3 cells treated with SJKJT. These findings indicate that SJKJT inhibits the proliferation of BxPC-3 cells through the extrinsic and intrinsic pathway, inducing apoptosis in vitro. Our study, using BxPC-3 human pancreatic cancer cells, demonstrates that SJKJT has potential as a chemotherapeutic agent for the treatment of pancreatic cancer. Further sutdies are warranted to fully elucidate its mechanisms of action.

Use of high-dose nandrolone aggravates septic shock in a mouse model

Nandrolone, an anabolic‐androgenic steroid, is widely misused by athletes who wish to rapidly increase muscle mass and performance. An increasing number of reports have indicated that nandrolone may affect and modulate the immune system. This study aimed to investigate the effects of nandrolone on septic shock‐caused immune responses and the cellular mechanism of action using a sepsis murine model. Before septic shock induction, BALB/c mice were given a high dose of nandrolone or peanut oil only. After septic shock induction, mice were sacrificed at different time points. Their blood and tissue specimens were analyzed. It was found that the high‐dose nandrolone group had significantly increased mortality compared with the control group (p < 0.001). The serum malondialdehyde level was significantly increased in the high‐dose group compared with the control group. Animals administered a high dose of nandrolone had significantly increased hepatic tumor necrosis factor‐α or splenic interferon‐γ at 0 and 6 hours. In lung tissue, insulin‐like growth factor‐1, insulin‐like growth factor binding proteins (IGFBPs) and insulin‐like growth factor‐1 receptor, and IGFBP1 and IGFBP2 mRNA expression were increased in the high‐dose nandrolone group at 6 hours. Nandrolone abuse may hasten the death of patients with septic shock and may aggravate septic shock in mice.