• Asian Pacific Journal of Cancer Prevention
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• v.15 no.14
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• pp.5691-5696
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• 2014

Background: Many clinical trials have been conducted to evaluate sorafenib for the treatment of advanced NSCLC, but the results for efficacy have been inconsistent. The aim of this study was to evaluate the efficacy and safety of sorafenib in patients with advanced NSCLC in more detail by meta-analysis. Methods: This meta-analysis of randomized controlled trials (RCTs) was performed after searching PubMed, EMBASE, ASCO Abstracts, ESMO Abstracts, and the proceedings of major conferences for relevant clinical trials. Two reviewers independently assessed the quality of the trials. Outcomes analysis were disease control rate (DCR), progression- free survival (PFS), overall survival (OS) with 95% confidence intervals (CI) and major toxicity. Subgroup analysis was conducted according to sorafenib monotherapy, in combination with chemotherapy or EGFR-TKI to investigate the preferred therapy strategy. Results: Results reported from 6 RCTs involving 2, 748 patients were included in the analysis. Compared to sorafenib-free group, SBT was not associated with higher DCR (RR 1.31 (0.96- 1.79), p=0.09), PFS (HR 0.82 (0.66-1.02), p=0.07) and OS (HR 1.01 (0.92-1.12), p=0.77). In terms of subgroup results, sorafenib monotherapy was associated with significant superior DCR and longer PFS, but failed to show advantage with regard to OS. Grade 3 or greater sorafenib-related adverse events included fatigue, hypertension, diarrhea, oral mucositis, rash and HFSR. Conclusions: SBT was revealed to yield no improvement in DCR, PFS and OS. However, sorafenib as monotherapy showed some activity in NSCLC. Further evaluation may be considered in subsets of patients who may benefit from this treatment. Sorafenib combined inhibition therapy should be limited unless the choice of platinum-doublet regimen, administration sequence or identification of predictive biomarkers are considered to receive better anti-tumor activity and prevention of resistance mechanisms.

• Journal of Life Science
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• v.15 no.3 s.70
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• pp.406-414
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• 2005

The genetic instability of cancer cells may be related to inappropriately activated DNA repair pathways. In present study, the modulated expression of DNA-dependent protein kinase (DNA-PK), a major DNA repair protein, in human cancer metastatic cells was tested. The expressions of Ku70/80, regulatory subunit of DNA-PK, and the Ku DNA-binding activity in various highly metastatic cell lines were higher than those in each parental cell line. Also, the expression of DNA-PKcs, catalytic subunit of DNA-PK, and the kinase activity of the whole DNA-PK complex in highly metastatic cells were significantly increased as compared to those of parental cells, suggesting that the enhanced DNA repair capacity of metastatic cells could be associated with aberrant use of DNA repair, which may mediate tumor progression and metastatic potential. Increased EGFR (epidermal growth factor receptor) signaling has been associated with tumor invasion and metastasis, and the linkage between EGFR-mediated signaling and DNA-PK has been suggested. This study showed that PKI166, the new EGFR tyrosine kinase inhibitor, modulated the expressions of Ku70/80 and DNA-PKcs and also revealed the chemosensitization effect of PKI166 against metastatic cells may be in part due to inhibition of Ku70/80. These results suggest that interference in EGFR signaling by EGFR inhibitor resulted in the impairment of DNA repair activity, and thus DNA-PK could be possible molecular targets for therapy against metastatic cancer cells.

• Toxicological Research
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• v.27 no.4
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• pp.253-259
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• 2011

Transforming growth factor ${\beta}$ (TGF-${\beta}$) is involved in cellular processes including growth, differentiation, apoptosis, migration, and homeostasis. Generally, TGF-${\beta}$ is the inhibitor of cell cycle progression and plays a role in enhancing the antagonistic effects of many growth factors. Unlike the antiproliferative effect of TGF-${\beta}$, E2, an endogeneous estrogen, is stimulating cell proliferation in the estrogen-dependent organs, which are mediated via the estrogen receptors, $ER{\alpha}$ and $ER{\beta}$, and may be considered as a critical risk factor in tumorigenesis of hormone-responsive cancers. Previous researches reported the cross-talk between estrogen/$ER{\alpha}$ and TGF-${\beta}$ pathway. Especially, based on the E2-mediated inhibition of TGF-${\beta}$ signaling, we examined the inhibition effect of 4-tert-octylphenol (OP) and 4-nonylphenol (NP), which are well known xenoestrogens in endocrine disrupting chemicals (EDCs), on TGF-${\beta}$ signaling via semi-quantitative reverse-transcription PCR. The treatment of E2, OP, or NP resulted in the downregulation of TGF-${\beta}$ receptor2 (TGF-${\beta}$ R2) in TGF-${\beta}$ signaling pathway. However, the expression level of TGF-${\beta}1$ and TGF-${\beta}$ receptor1 (TGF-${\beta}$ R1) genes was not altered. On the other hand, E2, OP, or NP upregulated the expression of a cell-cycle regulating gene, c-myc, which is a oncogene and a downstream target gene of TGF-${\beta}$ signaling pathway. As a result of downregulation of TGF-${\beta}$ R2 and the upregulation of c-myc, E2, OP, or NP increased cell proliferation of BG-1 ovarian cancer cells. Taken together, these results suggest that E2 and these two EDCs may mediate cancer cell proliferation by inhibiting TGF-${\beta}$ signaling via the downregulation of TGF-${\beta}$ R2 and the upregulation of c-myc oncogene. In addition, it can be inferred that these EDCs have the possibility of tumorigenesis in estrogen-responsive organs by certainly representing estrogenic effect in inhibiting TGF-${\beta}$ signaling.

• Journal of Life Science
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• v.29 no.1
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• pp.105-111
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• 2019

In recent years, progress has been made in the search for the development of new anti-cancer agents by employing specific inhibitors of histone deacetylase (HDAC)-6 to block signal transduction pathways in cancer cells. This study examined the effects of tubastatin A (TubA), an HDAC-6 inhibitor, on the growth and development of immature oocytes in murine ovaries using RNA sequencing analysis. The results from a gene set enrichment analysis (GSEA) indicated that the expression of most of the gene sets involved in the cell cycle and control and progression of meiosis decreased in the TubA-treated group as compared with that in germinal vesicle (GV) stage oocytes. In addition, an ingenuity pathway analysis (IPA) suggested that TubA not only caused increased expression of p53 and pRB and decreased expression of CDK4/6 and cyclin D but also caused elevated expression of genes involved in the control of the DNA check point in G2/M stage oocytes. These results suggest that TubA may induce cell cycle arrest and apoptosis through the induction of changes in the expression of genes involved in signal transduction pathways associated with DNA damage and the cell cycle of immature oocytes in the ovary.

• Biomolecules & Therapeutics
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• v.30 no.6
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• pp.553-561
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• 2022

Chronic myeloid leukemia (CML) is a slowly progressing hematopoietic cell disorder. Sphingosine kinase 1 (SPHK1) plays established roles in tumor initiation, progression, and chemotherapy resistance in a wide range of cancers, including leukemia. However, small-molecule inhibitors targeting SPHK1 in CML still need to be developed. This study revealed the role of SPHK1 in CML and investigated the potential anti-leukemic activity of hirsuteine (HST), an indole alkaloid obtained from the oriental plant Uncaria rhynchophylla, in CML cells. These results suggest that SPHK1 is highly expressed in CML cells and that overexpression of SPHK1 represents poor clinical outcomes in CML patients. HST exposure led to G2/M phase arrest, cellular apoptosis, and downregulation of Cyclin B1 and CDC2 and cleavage of Caspase 3 and PARP in CML cells. HST shifted sphingolipid rheostat from sphingosine 1-phosphate (S1P) towards the ceramide coupled with a marked inhibition of SPHK1. Mechanistically, HST significantly blocked SPHK1/S1P/S1PR1 and BCR-ABL/PI3K/Akt pathways. In addition, HST can be docked with residues of SPHK1 and shifts the SPHK1 melting curve, indicating the potential protein-ligand interactions between SPHK1 and HST in both CML cells. SPHK1 overexpression impaired apoptosis and proliferation of CML cells induced by HST alone. These results suggest that HST, which may serve as a novel and specific SPHK1 inhibitor, exerts anti-leukemic activity by inhibiting the SPHK1/S1P/S1PR1 and BCR-ABL/PI3K/Akt pathways in CML cells, thus conferring HST as a promising anti-leukemic drug for CML therapy in the future.

• BMB Reports
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• v.56 no.10
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• pp.569-574
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• 2023

Aberrant DNA methylation plays a pivotal role in the onset and progression of colorectal cancer (CRC), a disease with high incidence and mortality rates in Korea. Several CRC-associated diagnostic and prognostic methylation markers have been identified; however, due to a lack of comprehensive clinical and methylome data, these markers have not been validated in the Korean population. Therefore, in this study, we aimed to obtain the CRC methylation profile using 172 tumors and 128 adjacent normal colon tissues of Korean patients with CRC. Based on the comparative methylome analysis, we found that hypermethylated positions in the tumor were predominantly concentrated in CpG islands and promoter regions, whereas hypomethylated positions were largely found in the open-sea region, notably distant from the CpG islands. In addition, we stratified patients by applying the CpG island methylator phenotype (CIMP) to the tumor methylome data. This stratification validated previous clinicopathological implications, as tumors with high CIMP signatures were significantly correlated with the proximal colon, higher prevalence of microsatellite instability status, and MLH1 promoter methylation. In conclusion, our extensive methylome analysis and the accompanying dataset offers valuable insights into the utilization of CRC-associated methylation markers in Korean patients, potentially improving CRC diagnosis and prognosis. Furthermore, this study serves as a solid foundation for further investigations into personalized and ethnicity-specific CRC treatments.

• Journal of Life Science
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• v.33 no.11
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• pp.876-886
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• 2023

In some cases of head and neck cancers (HNC), surgical interventions may result in the loss of organs and/or changes to their functions, thereby significantly affecting the patient's quality of life. As a result, the surgical treatment of HNC patients is often limited to specific cases, and alternative treatment modalities, such as chemotherapy, are considered. However, serious adverse effects caused by chemotherapy, such as severe nausea and vomiting, necessitate the need for the development of adjunctive methods to minimize patient suffering. Chuanxiong, Ligusticum chuanxiong (L. chuanxiong), is a natural herb used in Eastern medicine to treat cerebrovascular disorders and headaches. This study aimed to predict the effect and potential of L. chuanxiong as an auxiliary anticancer drug through network-based pharmacology and molecular docking analysis. The study results showed that 40 out of 41 genes of L. chuanxiong shared common targets of HNC and their proteins could be used to target HNC cells to prevent cancer progression. The results of the functional enrichment analysis confirmed that L. chuanxiong is associated with the neuroactive-ligand metabolism and neurotransmitter pathways, indicating its potential medicinal value as an adjuvant in HNC treatment. Lastly, our findings demonstrated that the active ingredient of L. chuanxiong, (Z)-Ligustilide, has the ATP binding site of heat shock protein 90, a protein known to promote the activation of cancer cells. These results suggest that L. chuanxiong is a promising candidate for developing auxiliary anticancer drugs, and further research could potentially lead to the discovery of newer and safer anti-cancer agents.

• Korean Journal of Radiology
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• v.22 no.3
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• pp.366-375
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• 2021

Objective: To evaluate the radiological tumor response patterns and compare the response assessments based on immune-based therapeutics Response Evaluation Criteria in Solid Tumors (iRECIST) and RECIST 1.1 in metastatic clear-cell renal cell carcinoma (mccRCC) patients treated with programmed cell death-1 (PD-1) inhibitors. Materials and Methods: All mccRCC patients treated with PD-1 inhibitors at Henan Cancer Hospital, China, between January 2018 and April 2019, were retrospectively studied. A total of 30 mccRCC patients (20 males and 10 females; mean age, 55.6 years; age range, 37-79 years) were analyzed. The target lesions were quantified on consecutive CT scans during therapy using iRECIST and RECIST 1.1. The tumor growth rate was calculated before and after therapy initiation. The response patterns were analyzed, and the differences in tumor response assessments of the two criteria were compared. The intra- and inter-observer variabilities of iRECIST and RECIST 1.1 were also analyzed. Results: The objective response rate throughout therapy was 50% (95% confidence interval [CI]: 32.1-67.9) based on iRECIST and 30% (95% CI: 13.6-46.4) based on RECIST 1.1. The time-to-progression (TTP) based on iRECIST was longer than that based on RECIST 1.1 (median TTP: not reached vs. 170 days, p = 0.04). iRECIST and RECIST 1.1 were discordant in 8 cases, which were evaluated as immune-unconfirmed PD based on iRECIST and PD based on RECIST 1.1. Six patients (20%, 6/30) had pseudoprogression based on iRECIST, of which four demonstrated early pseudoprogression and two had delayed pseudoprogression. Significant differences in the tumor response assessments based on the two criteria were observed (p < 0.001). No patients demonstrated hyperprogression during the study period. Conclusion: Our study confirmed that the iRECIST criteria are more capable of capturing immune-related atypical responses during immunotherapy, whereas conventional RECIST 1.1 may underestimate the benefit of PD-1 inhibitors. Pseudoprogression is not rare in mccRCC patients during PD-1 inhibitor therapy, and it may last for more than the recommended maximum of 8 weeks, indicating a limitation of the current strategy for immune response monitoring.

• Journal of the Korean Society of Radiology
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• v.81 no.2
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• pp.428-435
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• 2020

Herein, we report a case of synchronous bilateral triple negative invasive ductal breast carcinoma in a patient with discrepant pathologic response to neoadjuvant chemotherapy. Right and left breast cancer stages at the initial diagnosis were T1cN0M0 and T4dN3aM0, respectively. The patient was identified as a BRCA1 mutation carrier and treated with four cycles of adriamycin and cyclophosphamide, followed by four cycles of docetaxel. Bilateral breast cancer stages decreased with the first regimen. However, the bilateral breast cancers showed discrepant responses to chemotherapy with docetaxel. The right breast cancer showed a continuous tumor volume reduction while the left breast cancer showed marked progression. Finally, the tumor size was 0.3 cm and 12 cm in the right and left mastectomy specimens, respectively. As bilateral breast cancers of the same subtype may show discrepant responses to neoadjuvant chemotherapy, close monitoring and follow-up imaging are required to avoid delayed surgery.

• Radiation Oncology Journal
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• v.22 no.2
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• pp.77-90
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• 2004

Purpose: The purpose of this review Is to provide an update on novel radiation treatments for head and neck cancer Recent Findings: Despite the remarkable advances In chemotherapy and radiotherapy techniques, the management of advanced head and neck cancer remains challenging. Epidermal growth factor receptor (EGFR) Is an appealing target for novel therapies In head and neck cancer because not only EGFR activation stimulates many important signaling pathways associated with cancer development and progression, and importantly, resistance to radiation. Furthermore, EGFR overexpression Is known to be portended for a worse outcome in patients with advanced head and neck cancer. Two categories of compounds designed to abrogate EGFR signaling, such as monoclonal antibodies (Cetuxlmab) and tyrosine kinase inhibitors (ZD1839 and 051-774) have been assessed and have been most extensively studied In preclinical models and clinical trials. Additional TKIs In clinical trials include a reversible agent, Cl-1033, which blocks activation of all erbB receptors. Encouraging preclinical data for head and neck cancers resulted In rapid translation Into the clinic. Results from Initial clinical trials show rather surprisingly that only minority of patients benefited from EGFR inhibition as monotherapy or In combination with chemotherapy. In this review, we begin with a brief summary of erbB- mediated signal transduction. Subsequently, we present data on prognostic-predictive value of erbB receptor expression in HNC followed by preclinlcal and clinical data on the role of EGFR antagonists alone or in combination with radiation In the treatment of HNC. Finally, we discuss the emerging thoughts on resistance to EGFR biockade and efforts In the development of multiple-targeted therapy for combination with chemotherapy or radiation. Current challenges for investigators are to determine (1 ) who will benefit from targeted agents and which agents are most appropriate to combine with radiation and/or chemotherapy, (2) how to sequence these agents with radiation and/or cytotoxlc compounds, (3) reliable markers for patient selection and verification of effective blockade of signaling in vivo, and (4) mechanisms behind intrinsic or acquired resistance to targeted agents to facilitate rational development of multi-targeted therapy, Other molecuiar-targeted approaches In head and neck cancer were briefly described, Including angloenesis Inhibitors, farnesyl transferase inhibitors, cell cycle regulators, and gene therapy Summary: Novel targeted theraples are highly appealing in advanced head and neck cancer, and the most premising strategy to use them Is a matter of intense Investigation.