• Korean Journal of Clinical Laboratory Science
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• v.51 no.2
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• pp.221-234
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• 2019

Cancer is genetically, metabolically and infectiously induced life threatening disorder showing aggressive growing pattern with invasive tendency. In order to prevent this global menace from jeopardizing human life, enormous studies on carcinogenesis and treatment for chemotherapy resistance have been intensively researched. Hinokitiol (${\beta}$-thujaplicin) extracted from heart wood of cupressaceous is a well-known bioactive compound demonstrating anti-inflammation, anti-bacteria and anti-cancer effects on several cancer types via apoptosis and autophagy. This study proposed that hinokitiol activates transcription factor EB (TFEB) nuclear translocation for autophagy and lysosomal biogenesis regardless of nutrient condition in cancer cells. Mitophagy and ${\beta}$-catenin translocation into the nucleus under treatment of hinokitiol on non-small cell lung cancer (NSCLC) cells and HeLa cells were investigated. Hinokitiol exerted cytotoxicity on HeLa and HCC827 cells; moreover, artificially induced autophagy by overexpression of TFEB granted imperfect sustainability onto HeLa cells. Taken together, hinokitiol is the prominent autophagy inducer and activator of TFEB nuclear translocation. Alternative cancer therapy via autophagy is pros and cons since the autophagy in cancer cells is related to prevention and survival mechanism depending on nutrition. To avoid paradox of autophagy in cancer therapy, fine-tuned regulation and application of hinokitiol in due course for successful suppressing cancer cells are recommended.

• Toxicological Research
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• v.35 no.2
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• pp.167-179
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• 2019

Ovarian cancer is the fifth main cause of pre-senescent death in women. Although chemotherapy is generally an efficient treatment, its side effects and the occurrence of chemotherapeutic resistance have prompted the need for alternative treatments. In this study, ${\alpha}$-mangostin and apigenin were evaluated as possible anticancer alternatives to the chemotherapeutic drug doxorubicin, used herein as a positive control. The ovarian adenocarcinoma cell line SKOV-3 (ATCC No. HTB77) was used as model ovarian cancer cells, whereas the skin fibroblast line CCD-986Sk (ATCC No. CRL-1947) and lung fibroblast line WI-38 (ATCC No. CCL-75) were used as model untransformed cells. Apigenin and doxorubicin inhibited the growth of SKOV-3 cells in a dose- and time-dependent manner. After 72 hr exposure, doxorubicin was mostly toxic to SKOV-3 cells, whereas apigenin was toxic to SKOV-3 cells but not CCD-986Sk and WI-38 cells. ${\alpha}$-Mangostin was more toxic to SKOV-3 cells than to CCD-986Sk cells. A lower cell density, cell shrinkage, and more unattached (floating round) cells were observed in all treated SKOV-3 cells, but the greatest effects were observed with ${\alpha}$-mangostin. With regard to programmed cell death, apigenin caused early apoptosis within 24 hr, whereas ${\alpha}$-mangostin and doxorubicin caused late apoptosis and necrosis after 72 hr of exposure. Caspase-3 activity was significantly increased in ${\alpha}$-mangostin-treated SKOV-3 cells after 12 hr of exposure, whereas only caspase-9 activity was significantly increased in apigenin-treated SKOV-3 cells at 24 hr. Both ${\alpha}$-mangostin and apigenin arrested the cell cycle at the $G_2/M$ phase, but after 24 and 48 hr, respectively. Significant upregulation of BCL2 (apoptosis-associated gene) and COX2 (inflammation-associated gene) transcripts was observed in apigenin- and ${\alpha}$-mangostin-treated SKOV-3 cells, respectively. ${\alpha}$-Mangostin and apigenin are therefore alternative options for SKOV-3 cell inhibition, with apigenin causing rapid early apoptosis related to the intrinsic apoptotic pathway, and ${\alpha}$-mangostin likely being involved with inflammation.

• The Korean Journal of Pain
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• v.34 no.1
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• pp.27-34
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• 2021

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a major reason for stopping or changing anticancer therapy. Among the proposed pathomechanisms underlying CIPN, proinflammatory processes have attracted increasing attention. Here we assessed the role of prostaglandin D2 (PGD2) signaling in cisplatin-induced neuropathic pain. Methods: CIPN was induced by intraperitoneal administration of cisplatin 2 mg/kg for 4 consecutive days using adult male Sprague-Dawley rats. PGD2 receptor DP1 and/or DP2 antagonists were administered intrathecally and the paw withdrawal thresholds were measured using von Frey filaments. Spinal expression of DP1, DP2, hematopoietic PGD synthase (H-PGDS), and lipocalin PGD synthase (L-PGDS) proteins were analyzed by western blotting. Results: The DP1 and DP2 antagonist AMG 853 and the selective DP2 antagonist CAY10471, but not the DP1 antagonist MK0524, significantly increased the paw withdrawal threshold compared to vehicle controls (P = 0.004 and P < 0.001, respectively). Western blotting analyses revealed comparable protein expression levels in DP1 and DP2 in the spinal cord. In the CIPN group the protein expression level of L-PGDS, but not of H-PGDS, was significantly increased compared to the control group (P < 0.001). Conclusions: The findings presented here indicate that enhanced PGD2 signaling, via upregulation of L-PGDS in the spinal cord, contributes to mechanical allodynia via DP2 receptors in a cisplatin-induced neuropathic pain model in rats, and that a blockade of DP2 receptor activation may present a novel therapeutic target for managing CIPN.

• The Journal of the Korean bone and joint tumor society
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• v.18 no.1
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• pp.7-13
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• 2012

Purpose: The purpose of this study is to compare general survival rate and survival rate according to expectable prognostic factors by analyzing the result of treating a patient of squamous cell carcinoma. Materials and Methods: From Mar. 1999 to Feb. 2011, 151 patients were pathologically confirmed as squamous cell carcinoma of limbs and body in our hospital, and among those patients, 51 patients underwent the surgical treatment. This study included 41 patients who underwent the surgical treatment and were followed-up for more than 12 months. The mean age of population was 64.4 years. 31 males and 10 females were included. Wide excision with following skin grafts or flaps for reconstruction (29 cases) was mostly performed, but amputation (12 cases) was also performed for cases with extremities where resection margin was difficult to obtain and cases with neural or vascular invasion. 8 patients underwent chemotherapy or radiotherapy after resection, and 33 underwent the operation only. Stages were classified by AJCC Classification, survival rate was calculated by Kaplan-Meier method and survival rate of groups was compared by Log-rank test. For the expectable prognostic factors related to survival rate, location of primary lesion, cause of disease, pathologic grade, staging, surgical method, additional anticancer therapy were examined and each survival rate was compared. Results: The average follow-up period was 65.2 (12-132) months. Thirty patients survived out of 41 patients till last follow up. The overall survival rate in 5 years was 77%. Three cases (7.3%) had local recurrence, and 7 cases (17.0%) had metastasis. The average period of recurrence from operation was 27 (18-43) months. Possible prognostic factors such as location of primary lesion, cause of disease, pathologic grade, staging, additional anticancer therapy showed no significant difference in survival rates. However, patients with amputation showed significantly lower survival rate than those with wide excision. Conclusion: In analysis the results of treating 41 cases of squamous cell carcinoma, the overall 5-year survival rate was 77%. And, among the several prognostic factors, only the surgical method was significant statistically.

• Tuberculosis and Respiratory Diseases
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• v.52 no.5
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• pp.475-484
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• 2002

Background : Unresectable non-small cell lung cancer has a poor response to chemotherapy and has an unfortunate prognosis. More effective and less toxic cytotoxic agents are needed to improve the outcome of these patients. The efficacy and safety of vinorelbine monotherapy in these advanced lung cancer patients was evaluanted. Materials and Methods : Sixteen patients with non-small cell lung cancer in stage III or IV, who received vinorelbine alone as an initial anticancer chemotherapy from June 1996 to December 2000 were enrolled in this study. Vinorelbine was given intravenously at a dose 30mg/$m^2$ every week. Results : A mong the sixteen patients, six had a partial response(38%) and the median survival was 16 weeks. The median response duration was 27 weeks (95% CI 6-47), and the time to progression was 16 weeks(95% CI 6-26). Among a total of 112 cycles, neutropenia(WHO grade 3 or 4) and anemia(grade 3) occurred in 9% and 3%, respectively. Only 1 patient required hospitalization for neutropenic fever. Non-hematologic toxicity was minor and was easily controlled. Conclusion : Vinorelbine monotherapy was well tolerated, and moderately effective in patients with advanced non-small cell lung cancer.

• Tuberculosis and Respiratory Diseases
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• v.66 no.2
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• pp.93-97
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• 2009

Background: Belotecan (Camtobell, CKD-602, Chongkundang Pharm., Korea), a camptothecin derivative, has anticancer effects by inhibiting topoisomerase I such as topotecan. This study observed the response, survival and toxicity of belotecan monotherapy after the failure of etoposide and platinum (EP). Methods: Forty nine small cell lung cancer (SCLC) patients (M/F=41/8; age, 64.5${\pm}$7.6 (mean${\pm}$SD) years), who failed in their first line chemotherapy were enrolled in this study. Twenty one SCLC patients showed relapsed lung cancer more than 90 days after their priorEP chemotherapy (sensitive relapse group, SR) and 28 patients relapsed within 90 days (refractory relapse group, RR). Results: The response rate was 25%. Eleven patients showed partial responses and 5 patients could not be checked. The response rate of the SR and RR patients was similar. The relative dose intensity was lower in the responders (78${\pm}$15%) than non-responders (83${\pm}$13%, p=0.03). The median survival time (MST) was 10.3 months (290 days). The MST of the non-responders and responders was 186 days (95% CI; 67-305) and 401 days (95% CI; 234-568, p=0.07), respectively. The median progression free survival (MPFS) was similar in the SR (79 days) and RR (67 days) patients. Grade 3-4 neutropenia, anemia, and thrombocytopenia were observed in 59.6%, 12.8% and 23.4% of patients, respectively. Conclusion: The efficacy and survival were demonstrated in the second-line setting. However, a randomized comparative trial with topotecan will be needed.

• Journal of the Korean Society of Radiology
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• v.81 no.3
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• pp.688-700
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• 2020

Purpose To compare the incidence, survival rate, and CT findings of acute exacerbation (AE) of idiopathic pulmonary fibrosis (IPF) between patients with and without lung cancer. Materials and Methods From June 2004 to July 2018, 89 consecutive patients diagnosed with IPF were included. Among them, 26 patients had IPF with lung cancer (IPF-LCA), and 63 patients had IPF alone. The clinical characteristics and CT findings associated with IPF, lung cancer, and AE were reviewed. Surgery and chemotherapy were performed for 6 and 23 cases of lung cancer, respectively, as the first- or second-line anticancer treatment. The overall survival, CT findings, disease-free period before AE, and duration from the onset of AE to death were compared. Results The incidence of AE was 61.5% in the IPF-LCA group and 58.7% in the IPF group (p = 0.806). The mean overall survival in the IPF-LCA and IPF groups were 16.8 and 83.0 months, respectively (p < 0.001). The mean durations from the start of the lung cancer treatment to the onset of AE were 16.0 and 4.6 months in cases of surgical treatment and chemotherapy, respectively. In comparison of death from AE, the survival rate was significantly lower in the IPF-LCA group than in the IPF group (p = 0.008). In the CT findings associated with AE, the IPF-LCA group tended to have a peribronchial (p < 0.001) or asymmetric distribution (p = 0.016). Conclusion In patients with IPF who develop lung cancer, the rate of death from AE is higher than that in patients with IPF alone. They tend to have unusual CT patterns associated with AE, such as a peribronchial or asymmetric distribution.

• Tuberculosis and Respiratory Diseases
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• v.57 no.4
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• pp.351-357
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• 2004

Background : Paclitaxel is highly beneficial anticancer drug for the treatment of non-small cell lung cancer and has shown remarkable radiosensitizing effect in vitro. We evaluated whether concurrent chemoradiation therapy with weekly paclitaxel (60 $mg/m^2$) could be tolerated and effective in the treatment of locally advanced non-small cell lung cancer (NSCLC). Methods : Twenty-two stage III (IIIA:6, IIIB:16) NSCLC patients were treated with weekly administration of paclitaxel (60 $mg/m^2$) on days 1, 8, 15, 22, 29, and 36 in addition to concurrent radiation therapy of 54 Gy. After the initial phase of concurrent chemoradiation, patients received additional two cycles of consolidation chemotherapy with paclitaxel (175 $mg/m^2$)/cisplatin (75 $mg/m^2$) or paclitaxel (175 $mg/m^2$)/carboplatin (6AUC) every 3 weeks. Results : Overall response rate was 81.8% (18/22) with 9.1% (2/22) of complete response and 72.7% (16/22) of partial response rate. Two patients (9.1%) died of chemoradiation-induced pneumonitis after completion of therapy. In total, grade 3 toxicities included pneumonitis (22.7%), esophagitis (22.7%), neuropathy (13.6%), and neutropenia (13.6%). The median survival time was 15 months and 2-year overall survival were 31.8%. Conclusion : Concurrent chemoradiation therapy with weekly paclitaxel in locally advanced NSCLC showed good local response, but survival rate was not completely satisfactory due to potentially fatal chemoradiation-induced pneumonitis.

• The Journal of the Korean bone and joint tumor society
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• v.15 no.2
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• pp.111-121
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• 2009

Background: Osteosarcoma is one of the most common primary malignant tumors of bone occurring mainly in children and adolescents. Although surgery combined with chemotherapy has markedly improved patient survival during the last years, the use of anticancer drugs is still associated with serious problem, such as the frequent acquisition of drug-resistant phenotypes and occurrence of "secondary malignancies". Several solid tumors display enhanced expression of matrix metalloproteinases (MMPs), and recently clinical trials have been initiated on MMP-inhibitors. On the other hand, bisphosphonates (BPs) are inhibitors of bone resorption, and widely used to treat osteoclast-mediated bone diseases. Also they appear to possess direct antitumor activity. Methods: One osteosarcoma cell line (U2OS) was treated with ibandronate (0, 0.1, 1, $10{\mu}M$) for 48 hours. Cell viabilities were determined using MTT assay, the mRNA levels of MMP-2 and MT1-MMP were detected by reverse-transcription polymerase chain reaction, the amount of MMP-2 and MT1-MMP protein were measured by Westernblot, the activities of MMP-2 were observed by Gelatin zymography, and Matrigel invasion assays were used to investigate the invasive potential of osteosarcoma cell lines before and after ibandronate treatment. Results: The invasiveness of U2OS cell line was reduced dose-dependently following 48 hour treatment of up to $10{\mu}M$ of the ibandronate at which concentration no cytotoxicity occurred. Furthermore, the gelatinolytic activities and protein and mRNA levels of MMP-2 and MT1-MMP were also suppressed by increasing ibandronate concentrations. Conclusion: Given that MMP-2 is instrumental in tumor cell invasion, it is very likely that the reduction in osteosarcoma cell invasion by ibandronate is a consequence, at least in part, of suppressed expression of both MMP-2 and MT1-MMP. Isolation of a molecule (s) responsible for the bisphosphonate inhibition of tumor cell invasion would pave the way for the development of a new generation of metastasis inhibitors.

• Tuberculosis and Respiratory Diseases
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• v.51 no.2
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• pp.122-134
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• 2001

Background : Some chemotherapeutic drugs induce NF-${\kappa}B$ activation by degrading the $I{\kappa}B{\alpha}$ protein in cancer cells which contributes to anticancer drug resistance. We hypothesized that inhibiting $I{\kappa}B{\alpha}$ degradation would block NF-${\kappa}B$ activation and result in increased tumor cell mortality in response to chemotherapy. Methods : The "superrepressor" form of the NF-${\kappa}B$ inhibitor was transferred by an adenoviral vector (Ad-$I{\kappa}B{\alpha}$-SR) to the human lung cancer cell lines (NCI H157 and NCI H460). With a MIT assay, the level of sensitization to cisplatin and paclitaxel were measured. To confirm the mechanism, an EMSA and Annexin V assay were performed. Results : EMSA showed that $I{\kappa}B{\alpha}$-SR effectively blocked the NF-${\kappa}B$ activation induced by cisplatin. Transduction with Ad-$I{\kappa}B{\alpha}$-SR resulted in an increased sensitivity of the lung cancer cell lines to cisplatin and paclitaxel by a factor of 2~3 in terms of $IC_{50}$. Annexin-V analysis suggests that this increment in chemosensitivity to cisplatin probably occurs through the induction of apoptosis. Conclusion : The blockade of chemotherapeutics induced NF-${\kappa}B$ activation by inducing Ad-$I{\kappa}B{\alpha}$-SR, increased apoptosis and increasing the chemosensitivity of the lung cancer cell lines tested, subsequently. Gene transfer of $I{\kappa}B{\alpha}$-SR appears to be a new therapeutic strategy of chemosensitization in lung cancer.