• Title, Summary, Keyword: cancer chemotherapy resistance

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Serum miR-19a Predicts Resistance to FOLFOX Chemotherapy in Advanced Colorectal Cancer Cases

  • Chen, Qi;Xia, Hong-Wei;Ge, Xiao-Jun;Zhang, Yu-Chen;Tang, Qiu-Lin;Bi, Feng
    • Asian Pacific Journal of Cancer Prevention
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    • v.14 no.12
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    • pp.7421-7426
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    • 2013
  • Background: Colorectal cancer is the fourth most common cancer worldwide and the second leading cause of cancer-related death. FOLFOX is the most common regimen used in the first-line chemotherapy in advanced colorectal cancer, but only half of the patients respond to this regimen and we have almost no clue in predicting resistance in such first-line application. Methods: To explore the potential molecular biomarkers predicting the resistance of FOLFOX regimen as the first-line treatment in advanced colorectal cancer, we screened microRNAs in serum samples from drug-responsive and drug-resistant patients by microarrays. Then differential microRNA expression was further validated in an independent population by reverse transcription and quantitative real-time PCR. Results: 62 microRNAs expressing differentially with fold-change >2 were screened out by microarray analysis. Among them, 5 (miR-221, miR-222, miR-122, miR-19a, miR-144) were chosen for further validation in an independent population (N=72). Our results indicated serum miR-19a to be significantly up-regulated in resistance-phase serum (p=0.009). The ROC curve analysis showed that the sensitivity of serum miR-19a to discriminate the resistant patients from the response ones was 66.7%, and the specificity was 63.9% when the AUC was 0.679. We additionally observed serum miR-19a had a complementary value for cancer embryonic antigen (CEA). Stratified analysis further revealed that serum miR-19a predicted both intrinsic and acquired drug resistance. Conclusions: Our findings confirmed aberrant expression of serum miR-19a in FOLFOX chemotherapy resistance patients, suggesting serum miR-19a could be a potential molecular biomarker for predicting and monitoring resistance to first-line FOLFOX chemotherapy regimens in advanced colorectal cancer patients.

Update of Research on Drug Resistance in Small Cell Lung Cancer Chemotherapy

  • Chen, Yi-Tian;Feng, Bing;Chen, Long-Bang
    • Asian Pacific Journal of Cancer Prevention
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    • v.13 no.8
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    • pp.3577-3581
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    • 2012
  • Small cell lung cancer (SCLC) is characterized by a short cell doubling time, rapid progression and early occurrence of blood-borne and lymph metastasis. The malignancy is the highest of all lung cancer types. Although SCLC has a relatively good initial response to chemotherapy as well as radiotherapy, relapse or disease progression may occur quickly after the initial treatment. Drug resistance, especially multi-drug resistance, is the most important cause of failure of SCLC chemotherapy. This article provides a brief update of research on mechanisms of drug resistance in SCLC and reversal strategies.

Targeting Multidrug Resistance with Small Molecules for Cancer Therapy

  • Xia, Yan;Lee, Kyeong
    • Biomolecules & Therapeutics
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    • v.18 no.4
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    • pp.375-385
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    • 2010
  • Conventional cancer chemotherapy is seriously limited by tumor cells exhibiting multidrug resistance (MDR), which is caused by changes in the levels or activity of membrane transporters that mediate energy-dependent drug efflux and of proteins that affect drug metabolism and/or drug action. Cancer scientists and oncologists have worked together for some time to understand anticancer drug resistance and develop pharmacological strategies to overcome such resistance. Much focus has been on the reversal of the MDR phenotype by inhibition of ATP-binding cassette (ABC) drug transporters. ABC transporters are a family of transporter proteins that mediate drug resistance and low drug bioavailability by pumping various drugs out of cells at the expense of ATP hydrolysis. Many inhibitors of MDR transporters have been identified, and though some are currently undergoing clinical trials, none are in clinical use. Herein, we briefly review the status of MDR in human cancer, explore the pathways of MDR in chemotherapy, and outline recent advances in the design and development of MDR modulators.

Alkylglyceronephosphate Synthase (AGPS) Alters Lipid Signaling Pathways and Supports Chemotherapy Resistance of Glioma and Hepatic Carcinoma Cell Lines

  • Zhu, Yu;Liu, Xing-Jun;Yang, Ping;Zhao, Meng;Lv, Li-Xia;Zhang, Guo-Dong;Wang, Qin;Zhang, Ling
    • Asian Pacific Journal of Cancer Prevention
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    • v.15 no.7
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    • pp.3219-3226
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    • 2014
  • Chemotherapy continues to be a mainstay of cancer treatment, although drug resistance is a major obstacle. Lipid metabolism plays a critical role in cancer pathology, with elevated ether lipid levels. Recently, alkylglyceronephosphate synthase (AGPS), an enzyme that catalyzes the critical step in ether lipid synthesis, was shown to be up-regulated in multiple types of cancer cells and primary tumors. Here, we demonstrated that silencing of AGPS in chemotherapy resistance glioma U87MG/DDP and hepatic carcinoma HepG2/ADM cell lines resulted in reduced cell proliferation, increased drug sensitivity, cell cycle arrest and cell apoptosis through reducing the intracellular concentration of lysophosphatidic acid (LPA), lysophosphatidic acid-ether (LPAe) and prostaglandin E2 (PGE2), resulting in reduction of LPA receptor and EP receptors mediated PI3K/AKT signaling pathways and the expression of several multi-drug resistance genes, like MDR1, MRP1 and ABCG2. ${\beta}$-catenin, caspase-3/8, Bcl-2 and survivin were also found to be involved. In summary, our studies indicate that AGPS plays a role in cancer chemotherapy resistance by mediating signaling lipid metabolism in cancer cells.

Estrogen Receptor α Roles in Breast Cancer Chemoresistance

  • Xu, Chao-Yang;Jiang, Zhi-Nong;Zhou, Ying;Li, Jia-Jia;Huang, Li-Ming
    • Asian Pacific Journal of Cancer Prevention
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    • v.14 no.7
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    • pp.4049-4052
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    • 2013
  • Resistance to chemotherapy treatment, which may lead to limited efficacy of systemic therapy in breast cancer patients, is multifactorial. Among the mechanisms of resistance to chemotherapy treatment, there are those closely related to estrogen receptor ${\alpha}$, P-glycoprotein, multidrug resistance-related protein, glutathione S-transferase pi and topoisomerase-II. $ER{\alpha}$ is ligand-activated transcription factor that regulates gene expression and plays a critical role in endocrine signaling. In previous preclinical and clinical studies, positive $ER{\alpha}$ expression in breast cancer cells was correlated with decreased sensitivity to chemotherapy. This article reviews current knowledge on the predictive value of $ER{\alpha}$ with regard to response to chemotherapy. Better understanding of its role may facilitate patient selection of therapeutic regimens and lead to optimal clinical outcomes.

Nrf2 Overexpression Predicts Prognosis and 5-FU Resistance in Gastric Cancer

  • Hu, Xiu-Feng;Yao, Jun;Gao, She-Gan;Wang, Xin-Shuai;Peng, Xiu-Qing;Yang, Yan-Tong;Feng, Xiao-Shan
    • Asian Pacific Journal of Cancer Prevention
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    • v.14 no.9
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    • pp.5231-5235
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    • 2013
  • Objective: NF-E2-related factor 2 (Nrf2) is activated in several human malignancies. However, the role of Nrf2 in gastric cancer (GC) remains incompletely understood. In this study, we therefore analyzed associations of Nrf2 expression status with clinical features and chemotherapeutic resistance in GC. Materials and Methods: A total of 186 samples from GC patients who underwent gastrectomy were used for prognostic assessment. A further 142 samples from GC cases who received first-line combination chemotherapy were applied for investigation of chemoresistance. The Nrf2 expression was evaluated by immunohistochemistry in GC samples, and its relationship with clinicopathological parameters and chemotherapy sensitivity was analyzed. The effect of Nrf2 gene silencing on chemotherapy resistance was also examined by cell viability assay in vivo. Results: Of the 186 patients with GC, 104/186 (55.9%) showed high expression for Nrf2. The overexpression of Nrf2 was an independent predictor of overall survival [OS, hazard ratio (HR) 3.9; P=0.011] and disease-free survival (DFS, HR 4.3; P=0.002). The gene silencing of Nrf2 reduced resistance to cell death induced by 5-FU in GC cell lines. Conclusion: Our data show that Nrf2 is an independent prognostic factor in GC. Furthermore, Nrf2 confers resistance to chemotherapeutic drug 5-FU in GC cells. Taken together, Nrf2 is a potential prognostic marker and predictive for 5-FU resistance in GC.

Modulation of Multidrug Resistance in Cancer by P-Glycoprotein

  • Gadhe, Changdev G.;Cho, Seung Joo
    • Journal of the Chosun Natural Science
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    • v.4 no.1
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    • pp.23-30
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    • 2011
  • Multidrug resistance (MDR) is one of the main obstacles in the chemotherapy of cancer. MDR is associated with the over expression of P-glycoprotein (P-gp), resulting in increased efflux of chemotherapy from cancer cells. Inhibiting P-gp as a method to reverse MDR in cancer patients has been studied extensively, but the results have generally been disappointing. First-generation agents were limited by unacceptable toxicity, whereas second-generation agents had better tolerability but were confounded by unpredictable pharmacokinetic interactions and interactions with other transporter proteins. Third-generation inhibitors have high potency and specificity for P-gp. Furthermore, pharmacokinetic studies to date have shown no appreciable impact on drug metabolism and no clinically significant drug interactions with common chemotherapy agents. Third-generation P-gp inhibitors have shown promise in clinical trials. The continued development of these agents may establish the true therapeutic potential of P-gp-mediated MDR reversal.

Role of Neoadjuvant Chemotherapy in the Management of Advanced Ovarian Cancer

  • Zhao, Dan;Wu, Ling-Ying;Wang, Xiao-Bing;Li, Xiao-Guang
    • Asian Pacific Journal of Cancer Prevention
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    • v.16 no.6
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    • pp.2369-2373
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    • 2015
  • Objective: To analyze efficacy of neoadjuvant chemotherapy for advanced ovarian cancer. Materials and Methods: A total of 107 patients with advanced ovarian cancer undergoing cytoreductive surgery were divided into a neoadjuvant chemotherapy group (n=61) and a primary debulking group (n=46) and retrospectively analyzed. Platinum-based adjuvant chemotherapy was applied to both groups after cytoreductive surgery ande overall and progression-free survival times were calculated. Results: No significant difference was observed in duration of hospitalization ($20.8{\pm}6.1$ vs. $20.2{\pm}5.4$ days, p>0.05). The operation time of neoadjuvant chemotherapy group was shorter than the initial surgery group ($3.1{\pm}0.7$ vs. $3.4{\pm}0.8$ h, p<0.05). There were no significant differences in median overall survival time between neoadjuvant chemotherapy group and surgery group (42 vs. 55 months, p>0.05). Similarly, there was no difference in median progression-free survival between neoadjuvant chemotherapy group and surgery group (16 vs. 17 months, p>0.05). The surgical residual tumor size demonstrated no significant difference between initial surgery and neoadjuvant chemotherapy groups (p>0.05). Multivariate analysis showed that more than 3 cycles of regimen with neoadjuvant chemotherapy was associated with more resistance to chemotherapy compared with patients without receiving neoadjuvant chemotherapy (OR: 5.962, 95%CI: 1.184-30.030, p<0.05). Conclusions:Neoadjuvant chemotherapy can shorten the operation time. However, it does not improve survival rates of advanced ovarian cancer patients.

Development of Anticancer Prodrugs and Tumor Specific Adjuvant Prodrugs for Chemotherapy

  • Moon, Ki-Young
    • Proceedings of the Korean Society of Applied Pharmacology
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    • pp.8-9
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    • 2000
  • Despite the advances made in the past few decades in cancer chemotherapy, many conventional anticancer drugs display relatively poor selectivity for cancer cells. The nonselectivity of anticancer drugs and the development of anticancer drug resistance have been recognized as serious limitations in their clinical usefulness. Therefore, a major challenge in cancer chemotherapy is the development of new anticancer agents with improved selectivity for tumor cells as well as the prevention of the host cell resistance, both of which result in the improvement of therapeutic effect against cancer cells. Cyclophosphamide (CP), a widely used anticancer agent, is a prodrug that is activated by hepatic microsomal mixed-function oxidase (MFO) catalyzed C$_4$- hydroxylation. The resulting 4-hydroxycyclophosphamide (4-OH-CP) is converted to the ring-opened tautomer to aldophosphamide (Aldo) which subsequently undergoes a base- catalyzed ${\beta}$-elimination to generate cytotoxic phosphoramide mustard (PDA) and acrolein. The cytotoxic activity of CP is attributed to the aziridinium ion species derived from PDA that cross-links interstrand DNA.

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Epithelial-mesenchymal Transition is Associated with Acquired Resistance to 5-Fluorocuracil in HT-29 Colon Cancer Cells

  • Kim, A-Young;Kwak, Jae-Hwan;Je, Nam Kyung;Lee, Yun-hee;Jung, Young-Suk
    • Toxicological Research
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    • v.31 no.2
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    • pp.151-156
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    • 2015
  • 5-Fluorouracil (5-FU) is commonly used for the therapy of colon cancer; however, acquired resistance to 5-FU is a critical barrier to successful treatment and the primary cause of chemotherapy failure. Epithelial-mesenchymal transition (EMT) is a process whereby cells undergo alterations in morphology and molecular characteristics promoting tumor progression and metastasis. Accumulating evidence shows that transition from epithelial to mesenchymal phenotype in cancer cells is associated with their resistance to chemotherapy. However, it is still poorly understood whether EMT is involved in acquired resistance to 5-FU. In this study, we developed an in vitro cell model, 5-FU-resistant HT-29 colon cancer cells, and characterized the differences in cellular morphology and molecular alterations between parental and resistant cells. In accord with mesenchymal-like morphology of 5-FU-resistant HT-29 cells, the expression of the mesenchymal marker fibronectin was significantly increased in these cells in comparision with that in the parental cells. Of interest, we also found a marked increase in the expression of EMT-inducing transcription factors Twist, Zeb1, and Zeb2. Finally, 5-FU-resistant cells showed enhanced migration in comparison with parental HT-29. Taken together, these results indicate that EMT could be associated with 5-FU resistance acquired by HT-29 cells. A specific role of each transcription factor found in this study will require further investigation.