Chien Kai Wang

Aqueous Extract of Solanum nigrum Leaves Induces Autophagy and Enhances Cytotoxicity of Cisplatin, Doxorubicin, Docetaxel, and 5-Fluorouracil in Human Colorectal Carcinoma Cells

Colorectal cancer is a common cancer worldwide, and chemotherapy is a mainstream approach for advanced and recurrent cases. Development of effective complementary drugs could help improve tumor suppression efficiency and control adverse effects from chemotherapy. The aqueous extract of Solanum nigrum leaves (AE-SN) is an essential component in many traditional Chinese medicine formulas for treating cancer, but there is a lack of evidence verifying its tumor suppression efficacy in colorectal cancer. The purpose of this study is to evaluate the tumor suppression efficacy of AE-SN using DLD-1 and HT-29 human colorectal carcinoma cells and examine the combined drug effect when combined with the chemotherapeutic drugs cisplatin, doxorubicin, docetaxel, and 5-fluorouracil. The results indicated that AE-SN induced autophagy via microtubule-associated protein 1 light chain 3 A/B II accumulation but not caspase-3-dependent apoptosis in both cell lines. The IC50s after 48 hours of treatment were 0.541 and 0.948 mg/ml AE-SN in DLD-1 and HT-29, respectively. AE-SN also demonstrated a combined drug effect with all tested drugs by enhancing cytotoxicity in tumor cells. Our results suggest that AE-SN has potential in the development of complementary chemotherapy for colorectal cancer.

Aqueous Extract of Solanum nigrum Leaf Activates Autophagic Cell Death and Enhances Docetaxel-Induced Cytotoxicity in Human Endometrial Carcinoma Cells

Chemotherapy is the main approach in dealing with advanced and recurrent endometrial cancer. An effective complementary ingredient can be helpful in improving the clinical outcome. Aqueous extract of Solanum nigrum leaf (AE-SN) is a principal ingredient for treating cancer patients in traditional Chinese medicinal practice but lacks sufficient evidence to verify its tumor suppression efficacy. This study evaluated the antitumor effects of AE-SN and also assessed the synergistic effects of AE-SN with docetaxel On the human endometrial cancer cell lines, HEC1A, HEC1B, and KLE. The activation of apoptotic markers, caspase-3 and poly-ADP-ribose polymerase, and autophagic marker, microtubule-associated protein 1 light chain 3 A/B, wAS determined to clarify the cell death pathways responsible for AE-SN induced tumor cell death. Results indicated that AE-SN-treatment has significant cytotoxicity on the tested endometrial cancer cells with accumulation of LC3 A/B II and demonstrated a synergistic effect of AE-SN and docetaxel in HEC1A and HEC1B cells, but not KLE cells. In conclusion, AE-SN treatment was effective in suppressing endometrial cancer cells via the autophagic pathway and was also capable of enhancing the cytotoxicity of docetaxel in human endometrial cancer cells. Our results provide meaningful evidence for integrative cancer therapy in the future.

Fermented Wheat Germ Extract Induced Cell Death and Enhanced Cytotoxicity of Cisplatin and 5-Fluorouracil on Human Hepatocellular Carcinoma Cells

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death worldwide. Due to the difficulties of early diagnosis, curative treatments are not available for most patients. Palliative treatments such as chemotherapy are often associated with low response rate, strong adverse effects and limited clinical benefits for patients. The alternative approaches such as fermented wheat germ extract (FWGE) with anti-tumor efficacy may provide improvements in the clinical outcome of current therapy for HCC. This study aimed to clarify antitumor efficacy of FWGE and the combination drug effect of FWGE with chemotherapeutic agents, cisplatin and 5-fluorouracil (5-Fu) in human HCC cells, HepG2, Hep3B, and HepJ5. The present study indicated that FWGE exhibited potential to suppress HepG2, Hep3B, and HepJ5 cells, with the half maximal inhibitory concentrations (IC50) of FWGE were 0.494, 0.371 and 1.524 mg/mL, respectively. FWGE also induced Poly (Adenosine diphosphate ribose) polymerase (PARP) associated cell death in Hep3B cells. Moreover, the FWGE treatment further enhanced the cytotoxicity of cisplatin in all tested HCC cells, and cytotoxicity of 5-Fu in a synergistic manner in HepJ5 cells. Collectively, the results identified the anti-tumor efficacy of FWGE in HCC cells and suggested that FWGE can be used as a supplement to effectively improve the tumor suppression efficiency of cisplatin and 5-Fu in HCC cells.

Thrombomodulin mediates the progression of epithelial ovarian cancer cells

Thrombomodulin (TM), a natural anticoagulation factor, maintains circulation homeostasis in endothelial cells. TM has additional roles in modulating inflammation, thrombosis, and carcinogenesis. However, there is little information on the role of TM in the progression and metastasis of ovarian cancer. RNA silencing and cDNA expression vectors were used to manipulate target gene expression in ovarian cancer cells. Cell growth and migration were evaluated by an MTT assay, a wound-healing migration assay, a transwell migration assay, and a biosensor system. In this study, we found that TM silencing may enhance the growth rate of cells. The migratory ability of ovarian cancer cells was enhanced dramatically after TM silencing. TM overexpression in ovarian cells suppressed the proliferation and migration capability. Furthermore, we found that skov-3 cells treated with TM shRNA expressed high levels of fibronectin and vimentin and that the expression of these markers correlated positively with their migratory ability. Our results demonstrate that TM expression may regulate cell growth and migration in ovarian cancer cells. This finding suggests that TM may be a novel prognostic and therapeutic target for ovarian cancer.

Thrombomodulin mediates the migration of cervical cancer cells through the regulation of epithelial–mesenchymal transition biomarkers

Thrombomodulin (TM) has been shown to regulate many physiological and pathological processes, including inflammation, thrombosis, and tumor progression. TM is also a natural anticoagulant that maintains circulatory homeostasis in endothelial cells. However, little is known regarding the role of TM in the progression and metastasis of cervical cancer. TM-specific RNA interference and a cDNA expression vector were used to manipulate TM expression in cervical cancer cells. Cell growth and cell migration were evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, transwell migration assays, and a biosensor system. TM silencing did not affect the growth rate of the cells. However, cell migration was dramatically enhanced after silencing of TM in HeLa cells. The overexpression of TM in cervical cancer cells only slightly influenced their proliferative capacity. After overexpression of TM in HeLa cells, their migratory capability was suppressed. Furthermore, we found that the decreased expression of E-cadherin and increase of zeb-1 and snail expression in TM-silenced cells which may be correlated with the results of knocking-down TM increases the migratory ability in this study. Our results demonstrate that TM may slightly regulate the growth but played the important role in the migratory ability of cervical cancer cells, suggesting that TM could potentially serve as a novel prognostic and therapeutic target in cervical cancer.

Integrated Treatment of Aqueous Extract of Solanum nigrum-Potentiated Cisplatin- and Doxorubicin-Induced Cytotoxicity in Human Hepatocellular Carcinoma Cells

Chemotherapy is the main approach for treating advanced and recurrent hepatocellular carcinoma (HCC), but the clinical performance of chemotherapy is limited by a relatively low response rate, drug resistance, and adverse effects that severely affect the quality of life of patients. The aqueous extract of Solanum nigrum (AE-SN) is a crucial ingredient in some traditional Chinese medicine (TCM) formulas for treating cancer patients and exhibits antitumor effects in human HCC cells. Therefore, this study examined the tumor-suppression efficiency of AE-SN integrated with a standard chemotherapeutic drug, namely, cisplatin or doxorubicin, in human HCC cells, namely, Hep3B and HepJ5. The results suggested that the integrated treatment with AE-SN-potentiated cisplatin and doxorubicin induced cytotoxicity through the cleavage of caspase-7 and accumulation of microtubule-associated protein-1 light chain-3 A/1B II (LC-3 A/B II), which were associated with apoptotic and autophagic cell death, respectively, in both the Hep3B and HepJ5 cells. In conclusion, AE-SN can potentially be used in novel integrated chemotherapy with cisplatin or doxorubicin to treat HCC patients.

Glucose-regulated protein 94 modulates the therapeutic efficacy to taxane in cervical cancer cells

Cervical cancer is an important health issue for women worldwide, and the endoplasmic reticulum stress pathway is important for determining the chemotherapeutic response to cancer. However, the role of glucose-regulated protein 94 (GRP94) in taxane therapy for cervical cancer remains unclear. In this study, we generated GRP94 knockdown (GRP94-KD) Hela cells using short hairpin RNAs and found that GRP94-KD cells were resistant to taxane treatment in an MTT assay. Scrambled control cells demonstrated higher levels of apoptosis when treated with taxanes in comparison to GRP94-KD cells, as determined by cell cycle profiling, 4′,6-diamidino-2-phenylindole staining, and terminal deoxynucleotidyl transferase-mediated nick end labeling staining. Caspase 3 and caspase 7 activity was also higher in scrambled control cells treated with taxane in comparison to GRP94-KD cells. Moreover, we found that depletion of GRP94 altered the levels of the apoptosis-related proteins Bcl2 and Bad, leading to sensitivity to taxane. Exposure to taxane also induced the expression of Bad in scrambled cells but not in GRP94-KD cells. In addition, the expression of Bcl2 was increased dramatically in GRP94-KD cells, whereas only a small increase was observed in scrambled cells. Therefore, we conclude that silencing GRP94 may increase resistance to taxane treatment in cervical cancer cells by altering the activation of the apoptosis pathway. In addition, GRP94 may represent a key biomarker for determining the therapeutic efficacy of taxane treatment in cervical cancer patients.

Preclinical Evaluation on the Tumor Suppression Efficiency and Combination Drug Effects of Fermented Wheat Germ Extract in Human Ovarian Carcinoma Cells

Fermented wheat germ extract (FWGE) is a nutrient supplement and a potential antitumor ingredient for developing an integrated chemotherapy with standard chemotherapeutic drugs for treating ovarian cancer patients. In this study, we evaluated the tumor suppression efficiency of FWGE in human ovarian carcinoma cells, SKOV-3 and ES-2, and found the half-maximal inhibitory concentrations (IC50s) to be 643.76 μg/mL and 246.11 μg/mL after 48 h of FWGE treatment. FWGE treatment also induced programmed cell death by activating the caspase-7 cleavage in both SKOV-3 and ES-2 cells, but only caspase-3 and poly(adenosine diphosphate-ribose) polymerase cleavages were activated in SKOV-3 cells. Moreover, FWGE exhibited combination drug effects with cisplatin and docetaxel in SKOV-3 and ES-2 cells by enhancing the cytotoxicity of both drugs. In conclusion, we found that FWGE not only suppressed cell growth but also induced caspase-3-related and caspase-7-related cell death in human ovarian carcinoma cells. FWGE treatment further enhanced the cytotoxicity of cisplatin and docetaxel, suggesting that FWGE is a potential ingredient in the development of adjuvant chemotherapy with cisplatin or docetaxel for treating ovarian cancer patients.

Antitumor effects and biological mechanism of action of the aqueous extract of the camptotheca acuminata fruit in human endometrial carcinoma cells

The aqueous extracts of the leaves and fruit of Camptotheca acuminata have long been used in traditional Chinese medicine (TCM) for treating cancer patients. The chemotherapeutic drug, camptothecin (CPT), and related analogs were first isolated from C. acuminata in the 1970s. Although the antitumor effects of CPT have been characterized in recent years, the antitumor effects of aqueous extracts of C. acuminata have not been clarified. The aims of our current study were to determine the tumor-suppression efficiency of an aqueous extract of the fruit of C. acuminata (AE-CA) in the human endometrial carcinoma cell lines, HEC-1A, HEC-1B, and KLE, and compare its antitumor effects with those of CPT. Cell viability assays indicated that a dosage of AE-CA containing 0.28 mg/mL of CPT demonstrated enhanced cytotoxicity, compared with CPT treatment. The effects of AE-CA on the induction of cell cycle arrest, the accumulation of cyclin-A2 and -B1, and the activation of caspase-3 and caspase-7 were similar to those of CPT. Furthermore, AE-CA exhibited a synergistic effect on the cytotoxicity of cisplatin in HEC-1A and HEC-1B cells. These results indicated that AE-CA is a potent antitumor agent and can be combined with cisplatin for the treatment of human endometrial cancer.

Combination of Two Targeted Medications (Bevacizumab Plus Cetuximab) Improve the Therapeutic Response of Pancreatic Carcinoma.

AbstractThe objective of this study is to evaluate the efficacy and safety profiles of the targeted medications, bevacizumab and cetuximab, in combination with cytostatic drugs in patients with locally advanced or metastatic pancreatic cancer.In this retrospective phase 2 study, a total of 59 patients with pancreatic cancer were recruited and received conventional (gemcitabine, cisplatin, and fluorouracil) or targeted regimen (conventional plus bevacizumab and cetuximab for the first cycle) in 2-week intervals for four cycles. The primary end-point for this study was the overall response rate. Secondary end-points were progression-free survival and the safety profiles of the combined therapy.The median time-to-progression and overall survival were 3 and 7 months, respectively, in the conventional treatment group as well as 11 and 13 months, respectively, in the targeted medications treatment group. The most common adverse events in both treatment groups were nausea and vomiting. Moderate (Grade 2) nausea and vomiting were more common in the conventional group than the targeted group but severe (Grade 3) nausea and vomiting were more common in the targeted group.Bevacizumab and cetuximab in combination with gemcitabine, cisplatin, and fluorouracil may help lengthen overall survival up to six months for patients with pancreatic cancer.