• Journal of Life Science
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• v.30 no.8
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• pp.661-671
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• 2020

The resistance of cancer cells to anti-cancer drugs is the leading cause of chemotherapy failure. The clinical use of nonsteroidal anti-inflammatory drugs (NSAIDs) has been gradually extended to cancer treatment through combination with anti-cancer drugs. In the current study, we investigated whether NSAIDs including celecoxib (CCB), 2,5-dimethyl celecoxib (DMC), and ibuprofen (IBU) could enhance the cytotoxic effects of imatinib and TNF-related apoptosis inducing ligand (TRAIL) on human cancer cells. We found that the NSAIDs potentiated TRAIL and imatinib cytotoxicity against human hepatocellular carcinoma (HCC) cell lines SNU-354, SNU-423, SNU-449, and SNU-475/TR and against leukemic K562 cells with high level of CD44 (CD44^highK562), respectively. More specifically, CCB induced endoplasmic reticulum stress via up-regulation of ATF4/CHOP which is associated with the induction of autophagy against HCC and CD44^high K562 cells. NSAID-induced autophagic activity accelerated TRAIL cytotoxicity of HCC cells through up- and down-regulation of DR5 and c-FLIP, respectively. The NSAIDs also potentiated imatinib-induced cytotoxicity and apoptosis through down-regulation of markers in CD44^highK562 cells that express a stemness phenotype. Our results suggest that the ability of NSAIDs to induce autophagy could enhance the cytotoxicity of TRAIL and imatinib, leading to a reverse resistance to these drugs in the cancer cells. In conclusion, NSAIDs in combination with low-dose TRAIL or imatinib may constitute a novel clinical strategy that maximizes therapeutic efficacy of each drug and effectively reduces the toxic side effects.

• Journal of Life Science
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• v.13 no.5
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• pp.551-558
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• 2003

Hepatitis C Virus (HCV) is associated with a severe liver disease and increased frequency in the development of hepatocellular carcinoma. Overexpression of HCV core protein is known to transform fibroblast cells. Phospholipase D (PLD) activity is commonly elevated in response to mitogenic signals, and PLD has been also reported to be overexpressed and hyperactivated in some human cancer. The aim of this study was to understand how PLD can be regulated in HCV core protein-transformed NIH3T3 mouse fibroblast cells. We observed that in unstimulated state, basal PLD activity was higher in NIH3T3 cells overexpressing HCV core protein than in vector-transfected cells. Although expression of PLD and protein kinase C (PKC) in core protein-transformed cells was similar with that of control cells, phorbol 12-myristate 13-acetate (PMA), which is known to activate PKC, stimulated significantly PLD activity in core protein-transformed cells, compared with that of the control cells. PLD activity assay using PKC isozyme-specific inhibitor, and PKC translocation experiment showed that PKC-$\delta$ was mainly involved in the PMA-induced PLD activation in the core-transformed cells. Taken together, these results suggest that PLD might be implicated in core protein-induced transformation.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.12
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• pp.6257-6261
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• 2012

Objective: To investigate the safety and efficacy of transcatheter arterial chemoembolization (TACE), combined with portal vein embolization (PVE), and high intensity focused ultrasound (HIFU) sequential therapy in treating patients with hepatocellular carcinoma (HCC). Methods: Patients with inoperative HCC were treated by two methods: in the study group with TACE first, then PVE a week later, and then TACE+PVE every two months as a cycle, after 2~3 cycles finally HIFU was given; in the control group only TACE+PVE was given. Response (CR+PR), and disease control rate (CR+PR+SD), side effects, overall survival and time to progress were calculated. Results: Main side effects of both groups were nausea and vomiting. No treatment related death occurred. In the study group, 32 patients received TACE for overall 67 times, PVE 64 times, and HIFU 99 times; on average 2.1, 2 and 3.1 times for each patient, respectively. In the control group, 36 patients were given TACE 78 times and PVE 74 times, averaging 2.2 and 2.1 times per patient. Effective rate: 25.0% in study group and 8.3% in control group (p>0.05). Disease control rates were 71.9% and 44.4%, respectively (p<0.05). In patients with portal vein tumor thrombus, the rate reduced over 1/2 after treatment was 69.2%(9/13) in the study and 21.4%(3/14) in the control group (p<0.05). Rate of AFP reversion or decrease over 1/2 was 66.7%(16/24) in study and 37%(10/27) (p<0.05) in control group. Median survival time: 16 months in study and 10 months in control group. PFS was 7months in study and 3 months in control group. Log-rank test suggested that statistically significant difference exists between two groups (p=0.024). 1-, 2- and 3-year survival rates were 56.3%, 18.8% and 9.3% in study, while 30.6%, 5.6% and 0 in control group, respectively, with statistically significant difference between two groups (by Log-rank, p = 0.014). Conclusions: The treatment of TACE+PVE+HIFU sequential therapy for HCC increases response rate, prolong survival, and could thus be a safe and effective treatment for advanced cases.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.17
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• pp.7213-7218
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• 2014

Background: Egypt has one of the highest prevalences of hepatitis C virus (HCV) infection worldwide. Although the IL28B gene polymorphism has been shown to modify the course of chronic HCV infection, this has not been properly assessed in the Egyptian population. Materials and Methods: The IL28B rs12979860 single nucleotide polymorphism (SNP) was therefore examined in 256 HCV-infected Egyptian patients (group II) at different stages of disease progression and in 48 healthy volunteers (group I). Group II was subdivided into GII-A (chronic hepatitis patients, n=119), GII-B (post hepatitis cirrhosis, n=66) and GII-C (HCC on top of cirrhosis, n=71). Results: The C/T genotype was the commonest in all groups. It was more frequent in GI (52%) than in GII (48%). There was no significant difference in the frequency of C/T and C/C or T/T genotypes between groups and subgroups (p=0.82). Within the subgroups; the C/C genotype was more common in GII-B while C/T and T/T genotypes were more common in GII-C, though with no significant difference (p=0.59 and p=0.80). There was no significant association between IL28B rs12979860 SNP and viral load, ALT, AFP level, METAVIR scores for necro-inflammation and fibrosis, and Child-Pugh classification. Conclusions: 1) IL28Brs12979860 C/T genotype is the commonest genotype in HCV-associated CH and HCC in Egypt. 2) IL28Brs12979860 polymorphisms are not associated with disease progression or aggression (histological staging, severity of fibrosis in CH or the incidence of post-HCV HCC). 3) Differences in IL28Brs12979860 genotypes could be a consequence of environmental or ethnic variation.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.11
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• pp.6227-6231
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• 2013

In the past, hepatitis B virus (HBV) infection was endemic in the general Korean population. The association of HBV infection with the occurrence of liver cancer has been well demonstrated in several epidemiologic studies. While the mortality rates of liver cancer in Korea have decreased steadily over the last decade, the presence of hepatitis B surface antigen (HBsAg) in mothers remains high at 3-4%, and 25.5% of these HBsAg positive mothers are positive for hepatitis B e antigen (HBeAg). HBV infection caused almost a quarter of hepatocellular carcinoma (HCC) cases and one-third of deaths from HCC. These aspects of HBV infection prompted the Korean government to create a vaccination program against HBV in the early 1980s. In 1995, the Communicable Disease Prevention Act (CDPA) was reformed, and the government increased the number of HBV vaccines in the National Immunization Program (NIP), driving the vaccination rate up to 95%. In 2000, the National Health Insurance Act (NHIA) was enacted, which provided increased resources for the prevention of perinatal HBV infection. Then in 2002, the Korean government, in conjunction with the Korean Medical Association (KMA), launched an HBV perinatal transmission prevention program. The prevalence of HBsAg in children had been high (4-5%) in the early 1980s, but had dropped to below 1% in 1995, and finally reached 0.2% in 2006 after the NIP had been implemented. After the success of the NIP, Korea finally obtained its first certification of achievement from the Western Pacific Regional Office of the World Health Organization (WPRO-WHO) for reaching its goal for HBV control. An age-period-cohort analysis showed a significant reduction in the liver cancer mortality rate in children and adolescents after the NIP had been implemented. In addition to its vaccination efforts, Korea launched the National Cancer Screening Program (NCSP) for 5 leading sites of cancer, including the liver, in 1999. As a consequence of this program, the 5-year liver cancer survival rate increased from 13.2% (1996-2000) to 23.3% (2003-2008). The development of both the primary and secondary prevention for liver cancer including HBV immunization and cancer screening has been of critical importance.

• The Journal of Internal Korean Medicine
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• v.36 no.1
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• pp.58-68
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• 2015

Objectives : To evaluate the long-term survival effects of traditional Korean medicine (TKM) on refractory metastatic lung cancer and small cell lung cancer (SCLC), which have historically poor survival rates. Methods : A retrospective study was conducted using the medical records of two patients in Daejeon University hospital. The first patient, with SCLC, was treated from January 2000 to December 2009 and the other, with metastatic pulmonary cancer from primary hepatocellular carcinoma (HCC), was treated from September 2004 to February 2014. The patients were treated with herbal medicines at one-month intervals. During hospitalization, acupuncture and indirect moxibustion were performed concurrent with the administration of Western therapy. Treatment efficacy was assessed monthly using chest radiography, chest computed tomography, and laboratory examination data, and by measuring patient performance status. Results : Both patients exhibited a stable disease course for more than 9 years after the initial diagnosis of intractable lung cancer, suggesting that their disease status was controlled by TKM. Conclusions : We suggest that a combination of TKM with conventional Western therapy for refractory lung cancer patients is effective in controlling various symptoms related to lung cancer and improving quality of life, and may potentially prolong overall survival.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.14
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• pp.5635-5641
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• 2015

Background: Cirrhosis is regarded as a possible end stage of many liver diseases, including viral infection. It occurs when healthy liver tissue becomes damaged and is replaced by scar tissue and finally may lead to hepatocellular carcinoma. Interferons (IFNs)are two general categories, type I and II. Type I includes one beta interferon and over 20 different alpha interferons. Alpha interferons are very similar in how they work, interacting with other proteins on cells like receptors. The main objective of this study was to compare Mx gene productivity post different cell line treatment with imported and Egyptian biosimilar locally produced IFNs, as well as the efficacy of those tested IFNs. Also, an assessment was made of sensitivity of different cell lines as alternatives to that recommended for evaluation of antiviral activity. Materials and Methods: Different cell lines (Vero, MDBK and Wish) were employed to evaluate cytotoxicity using the MTT assay. Antiviral activity was evaluated compared with standard IFN against VSV, Indiana strain -156, on tested rh-IFNs (imported; innovated and Egyptian biosimilar locally produced IFNs) in the pre-treated cell lines previously mentioned. The virus was propagated in the Wish cell line as recommended. Finally we estimated up-regulation of the Mx gene as a biomarker. Results: Data recorded revealed that test IFNs were safe in test cell lines. Viability was around 100%. Locally tested interferon did not realize the international potency limits, while the imported one was accepted compared with the standard IFN. These results were the same either using infectivity titer reduction assay or crystal violet staining of residual non- infected cells. Mx protein production was cell type related and confirmed by the detected Mx gene expressed in imported and locally produced IFN pre-treated cell lines. The expression of the gene was arranged in the order of Vero> wish > MDBK for the imported IFN, while for the Egyptian biosimillar locally produced one it was MDBK> Vero> wish. With regard to the antiviral activity there was a significant difference of imported IFN potency compared with the locally produced IFN (P<0.05), the IFN potential (antiviral activity) was not cell line related and showed non-significant difference for each separate product. Conclusions: Vero cells can be used as an alternative cell line for evaluation of IFN potency in case of unavailable USP recommended cell lines. Alternative potency evaluation assay could be used and proved significant difference in IFN potency in case of local and imported agents. Evaluation of antiviral activity could be used in parallel to viral infectivity reduction assay for better accuracy. Mx gene can be used as a marker for IFN potential.

• Investigative Magnetic Resonance Imaging
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• v.17 no.1
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• pp.8-18
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• 2013

Purpose : The purpose of this study was to find and categorize the various magnetic resonance imaging (MRI) findings of spinal metastases that correlate with the type of primary cancer. Materials and Methods: We retrospectively reviewed gadolinium-enhanced magnetic resonance images of 30 patients with 169 spinal metastatic lesions from lung cancer (n = 56), breast cancer (n = 29), colorectal cancer (n = 20), hepatocellular carcinoma (HCC) (n = 17), and stomach cancer (n = 47). The size, location, extent of invasion, signal intensity, margin, enhancement pattern, and osteoblastic or osteolytic characteristics of each metastatic tumor were analyzed. Results: The metastatic lesions from HCC were larger than those from the other primary tumors (P < 0.05) except for colorectal cancer (P = 0.268). Well-defined metastatic tumor margins were more frequently seen in lung cancer and breast cancer (P < 0.01). All but HCC showed a tendency to invade the vertebral body rather than the posterior elements (P < 0.02). Colorectal cancer and HCC showed a tendency toward extraosseous invasion without statistical significance. HCC showed a characteristic enhancement pattern of 'worms-in-a-bag'. Rim enhancement with a sclerotic center was only seen in spinal metastases from stomach cancer. Conclusion: Despite many overlapping imaging features, spinal metastases of various primary tumors display some characteristic MRI findings that can help identify the primary cancer.

• Archives of Plastic Surgery
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• v.36 no.1
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• pp.33-37
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• 2009

Purpose: Liver transplantation is considered as the treatment of choice in many acute and chronic liver diseases, and it is becoming more common. Since successful microscopic anastomosis of hepatic artery is a crucial requirement of successful liver transplantation, we studied and analyzed the result of hepatic artery anastomosis of liver transplantation in our liver transplantation center. Methods: 145 liver transplantations were performed between February 2005 and May 2008. Male to female ratio of the liver transplantation recipients was 3.4 : 1. Anastomosis of portal vein, hepatic vein and biliary tract was performed by the general surgeon, and anastomosis of hepatic artery was performed by the plastic surgeon under the loupe or microscopic vision. After the hepatic artery was reconstructed, anastomosed site status and flow were checked with Doppler ultrasonography intraoperatively and with contrast enhanced CT or angiography postoperatively if necessary. Results: Out of 145 liver transplantations, cadaveric liver donor was used 37 cases and living donor liver transplantation was performed 108 cases including the 2 dual donor liver transplantations. As for the baseline diseases that resulted in the liver transplantation, there were 57 cases of liver cirrhosis and hepatocellular carcinoma due to hepatitis B, taking up the greatest proportion. Single donor hepatic artery was used in 114 cases, and mean artery diameter was 2.92 mm and mean artery length was 24.25 mm. Hepatic artery was used as the recipient artery in every case except the 8 cases in which gastroepiploic artery was used as alternative. Out of 145 cases of hepatic artery anastomosis, 3 cases resulted in the thrombosis of the hepatic artery, requiring thrombectomy and re - anastomosis. In all 3 cases, thrombosis was found in left hepatic artery and there was no past history of hepatic artery chemoembolization. Conclusion: Incidence of hepatic artery thrombosis after the anastomosis of hepatic artery during liver transplantation was 2.1%, which is considered sufficiently low.

• The Korean Journal of Nuclear Medicine
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• v.30 no.4
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• pp.516-523
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• 1996

The purpose of this study was to evaluate the clinical usefulness of I-123 MIBG scintigraphy with early planar and SPECT image in the diagnosis of neuroendocrine tumors. We reviewed I-123 MIBG scintigraphies of 21 patients who had been suspected to have neuroendocrine tumors by CT or MRI findings. Early 4 hour planar and SPECT images were obtained in all patients and delayed (13-24 hour) planar images were performed in 17 patients. Final diagnoses were made by surgery, biopsy, or clinical follow up. Twelve patients were confirmed to have neuroendocrine tumors. With 4 hour planar and SPECT images, there were 9 true positives(6 pheochromocytomas, 1 paraganglioma, 1 neuroblastoma, and 1 medullary cancer of the thyroid), 8 true negatives(1 adrenal cortical adenoma, 1 malignant fibrous histiocytoma, 1 adenoma in colon and 5 benign nonfunctioning adrenal tumors), 1 false positive(hepatocellular carcinoma) and 3 false negatives(1 recurred medullary cancer of the thyroid, 1 liver metastasis of carcinoid tumor and 1 ganglioneuroma). The sensitivity and specificity of I-123 MIBG scintigraphy were 75% and 89%, respectively. SPECT images provided good anatomical correlation with CT or MRI. Delayed images showed increased tumor to background ratio in 5 out of 8 true positive patients, but did not change the diagnosis. In conclusion, early 4 hour images with I-123 MIBG is clinically convenient and useful method in the detection of neuroendocrine tumors, and SPECT images can provide good anatomical correlation with CT or MRI.