Exploring age-standardized cancer incidence rates and regional disparities: A retrospective cohort study of 8 major cancers in South Korea.

BACKGROUND: We analyzed trends in cancer incidence and regional disparities of eight major types of cancer in Korea. METHODS: This retrospective cohort study used the data of 17 cities/provinces from the Korea Central Cancer Registry (1999-2020) in South Korea. Age-standardized incidence rates (per 100,000 person-years), between-group variance (per 100,000 person-years)2, and annual percentage changes ( %) were calculated for the eight most common malignancies. Joinpoint regression was utilized to identify the points at which significant changes occur in cancer incidence or regional disparity trends over time to characterize these trends. RESULTS: The incidence of stomach cancer decreased as regional disparity decreased and that of colorectal cancer initially increased but recently declined, showing fluctuations in regional disparity. The incidence and regional disparity in liver cancer decreased. The incidence of lung cancer remained stable, with reduced regional disparities. The incidence of breast cancer rose with increasing regional disparity, whereas the incidence of cervical cancer decreased, accompanied by decreased regional disparity. A significant increase in prostate cancer was found, with initially reduced regional disparities but later showed a resurgence. The incidence of thyroid cancer fluctuated alongside variations in regional disparities. CONCLUSION: This study revealed cancer incidence and regional variations in each cancer type in Korea. More studies are needed to understand the underlying factors and potential interventions for reducing cancer incidence and addressing regional disparity.

Enhanced Postsurgical Cancer Treatment Using Methacrylated Glycol Chitosan Hydrogel for Sustained DNA/Doxorubicin Delivery and Immunotherapy.

Background: Cancer recurrence and metastasis are major contributors to treatment failure following tumor resection surgery. We developed a novel implantable drug delivery system utilizing glycol chitosan to address these issues. Glycol chitosan is a natural adjuvant, inducing dendritic cell activation to promote T helper 1 cell immune responses, macrophage activation, and cytokine production. Effective antigen production by dendritic cells initiates T-cell-mediated immune responses, aiding tumor growth control. Methods: In this study, we fabricated multifunctional methacrylated glycol chitosan (MGC) hydrogels with extended release of DNA/doxorubicin (DOX) complex for cancer immunotherapy. We constructed the resection model of breast cancer to verify the anticancer effects of MGC hydrogel with DNA/DOX complex. Results: This study demonstrated the potential of MGC hydrogel with extended release of DNA/DOX complex for local and efficient cancer therapy. The MGC hydrogel was implanted directly into the surgical site after tumor resection, activating tumor-related immune cells both locally and over a prolonged period of time through immune-reactive molecules. Conclusions: The MGC hydrogel effectively suppressed tumor recurrence and metastasis while enhancing immunotherapeutic efficacy and minimizing side effects. This biomaterial-based drug delivery system, combined with cancer immunotherapy, can substantial improve treatment outcomes and patient prognosis.

The Impact of Neighborhood Deprivation on the Survival Rates of Patients with Cancer in Korea.

The objective of this study is to investigate the correlation between the neighborhood deprivation index and survival rates of cancer patients in Korea. In this study, 5-year age-standardized survival rates of patients with cancer were determined using the National Cancer Cohort from 2014 to 2018 in Korea. The primary cancer sites were the stomach, colorectum, liver, lung, breast, cervix, prostate, and thyroid. Disparities were measured, and their impact on the overall survival rates was assessed using the Korean version of the Neighborhood Deprivation Index. Pearson's correlation coefficient was calculated to determine the strength of the correlation. The study cohort comprised 726,665 patients with cancer, of whom 50.7% were male. The predominant primary cancer sites were the stomach (n = 138,462), colorectum (n = 125,156), and thyroid gland (n = 120,886). Urban residents showed better survival outcomes than those situated in rural areas. The most deprived quartile had the lowest survival rate, while the least deprived quartile had the highest (p < 0.001). Most cancer types revealed significant correlations between neighborhood deprivation and 5-year age-standardized overall survival, with lung cancer showing the most substantial negative correlation (r = -0.510), followed by prostate cancer (r = -0.438). However, thyroid cancer showed only a marginal correlation (p = 0.069). The results of this study suggested that neighborhood deprivation is closely linked to disparities in overall survival across various types of cancer. A substantial negative correlation between the neighborhood deprivation index and all-cause mortality for lung and prostate cancer, as compared to breast and cervical cancers covered by the National Cancer Screening Program, may reinforce the need to address healthcare access and improve the early detection of cancer in socioeconomically deprived neighborhoods.

Disparities in Cancer Incidence across Income Levels in South Korea.

BACKGROUND: Recent nationwide studies of disparities in cancer incidence by income are scarce in Korea. This study investigated such disparities in cancer incidence and the stage at cancer diagnosis across income groups in Korea. METHODS: This study utilized data from a national cancer database, specifically focusing on cases recorded in the year 2018. Income levels were categorized into quintiles according to the insurance premium paid in addition to the Medicaid benefit. The slope index of inequality (SII) and relative index of inequality (RII) were used to measure absolute and relative differences in cancer incidence by income. A multivariable logistic regression was performed to estimate the risk of a distant stage at cancer diagnosis. RESULTS: The total number of cases of incident cancer was 223,371 (men: 116,320, women: 107,051) with shares of the total of 29.5% (5Q), 20.4% (4Q), 16.0% (3Q), 13.5% (2Q), 15.6% (1Q), and 5% (Medicaid). The most common cancer type was thyroid cancer, followed by gastric and colorectal cancers. The age-standardized incidence rate for all cancers was lowest in the highest income group, but the SII was not statistically significant (SII: -35.7), and the RII was -0.07. Colorectal and cervical cancers had lower incidence rates for higher income groups, while thyroid and prostate cancers had higher incidence rates for higher income groups. The odds ratio for a distant stage at diagnosis for all cancers increased for lower income groups relative to 5Q. CONCLUSIONS: Disparities in cancer incidence in a Korean population differed by cancer type, and lower income was a significant predictor of a distant stage at diagnosis for cancers overall. These results emphasize the need for further study of the underlying causes of disparities in cancer incidence and the stage at diagnosis, as well as the need for interventions to mitigate these disparities.

Socioeconomic differences in the perception of inequalities in healthcare utilization and health in South Korea.

This study investigated the lay perception of inequalities in society, healthcare utilization, and health in Korea. We also examined the association between socioeconomic status (SES) and perception of inequalities. Data from an online survey on the perception of health and healthcare inequalities related to cancer conducted between October 19, 2021, and November 12, 2021, were used. Data of 3,769 participants aged 20 to 74 years from 17 provinces were analyzed. We examined the perceived level of inequalities according to SES or residential area using frequency analysis, a t-test or analysis of variance (ANOVA), multiple linear regression analysis, and multiple logistic regression analysis. The mean score for perception of social inequality was 5.99 [Standard Deviation (SD) = 1.95] and that for perception of healthcare utilization inequality was 4.75 (SD = 1.96). The perception rate of health inequality according to SES and residential area was approximately 59 % and 61 %, respectively. Higher the income level, lower the level of perception of social inequalities ß = -0.22, p < 0.01). Higher the education level, higher the level of perception of healthcare utilization inequalities (ß = 0.21, p < 0.01). Higher the education level, higher the level of perception of health inequalities according to SES or residential area [adjusted odds ratio (aOR): 2.33 (95 % CI: 1.48, 3.66); aOR: 2.73 (95 % CI: 1.73, 4.31)]. Socioeconomic inequalities were observed in the perception of inequalities in healthcare utilization and health. Policymakers should establish policies to bridge the gap between perceived healthcare utilization inequalities and health inequalities. Future research should investigate the perception of healthcare utilization and health inequalities.

Impact of health disparities on national breast cancer screening participation rates in South Korea.

Socioeconomic barriers to cancer screening exist at a regional level. The deprivation index is used to estimate socioeconomic gradients and health disparities across different geographical regions. We aimed to examine the impact of deprivation on breast cancer screening participation rates among South Korean women. Municipal breast cancer screening participation rates in women were extracted from the National Cancer Screening Information System and linked to the Korean version of the deprivation index constructed by the Korea Institute for Health and Social Affairs. A generalised linear mixed model was employed to investigate the association between the deprivation index and age-standardised breast cancer screening participation rates in 2005, 2012, and 2018. Participation rates increased gradually across all age groups from 2005 to 2018. Participants in their 60 s consistently had one of the highest participation rates (2005: 30.37%, 2012: 61.57%, 2018: 65.88%). In 2005, the most deprived quintile had a higher estimate of breast cancer screening participation than the least deprived quintile (2nd quintile; estimate: 1.044, p = 0.242, 3rd quintile; estimate: 1.153, p = 0.192, 4th quintile; estimate: 3.517, p = 0.001, 5th quintile; estimate: 6.913, p = < 0.0001). In 2012, the participation rate also increased as the level of deprivation increased. There were no statistically meaningful results in 2018. Regions with high deprivation have a higher participation rate in breast cancer screening. The role of health disparities in determining cancer outcomes among women in Korea requires further examination.

Single-cell RNA sequencing reveals characteristics of myeloid cells in post-acute sequelae of SARS-CoV-2 patients with persistent respiratory symptoms.

Background: Although our understanding of the immunopathology and subsequent risk and severity of COVID-19 disease is evolving, a detailed account of immune responses that contribute to the long-term consequences of pulmonary complications in COVID-19 infection remains unclear. Few studies have detailed the immune and cytokine profiles associated with post-acute sequelae of SARS-CoV-2 infection (PASC) with persistent pulmonary symptoms. The dysregulation of the immune system that drives pulmonary sequelae in COVID-19 survivors and PASC sufferers remains largely unknown. Results: To characterize the immunological features of pulmonary PASC (PPASC), we performed droplet-based single-cell RNA sequencing (scRNA-seq) to study the transcriptomic profiles of peripheral blood mononuclear cells (PBMCs) from a participant naïve to SARS-CoV-2 (Control) (n=1) and infected with SARS-CoV-2 with chronic pulmonary symptoms (PPASC) (n=2). After integrating scRNA-seq data with a naïve participant from a published dataset, 11 distinct cell populations were identified based on the expression of canonical markers. The proportion of myeloid-lineage cells ([MLCs]; CD14+/CD16+monocytes, and dendritic cells) was increased in PPASC (n=2) compared to controls (n=2). MLCs from PPASC displayed up-regulation of genes associated with pulmonary symptoms/fibrosis, while glycolysis metabolism-related genes were downregulated. Similarly, pathway analysis showed that fibrosis-related (VEGF, WNT, and SMAD) and cell death pathways were up-regulated, but immune pathways were down-regulated in PPASC. Further comparison of PPASC with scRNA-seq data with Severe COVID-19 (n=4) data demonstrated enrichment of fibrotic transcriptional signatures. In PPASC, we observed interactive VEGF ligand-receptor pairs among MLCs, and network modules in CD14+ (cluster 4) and CD16+ (Cluster 5) monocytes displayed a significant enrichment for biological pathways linked to adverse COVID-19 outcomes, fibrosis, and angiogenesis. Further analysis revealed a distinct metabolic alteration in MLCs with a down-regulation of glycolysis/gluconeogenesis in PPASC compared to SARS-CoV-2 naïve samples. Conclusion: Analysis of a small scRNA-seq dataset demonstrated alterations in the immune response and cellular landscape in PPASC. The presence of elevated MLC levels and their corresponding gene signatures associated with fibrosis, immune response suppression, and altered metabolic states suggests a potential role in PPASC development.

Cancer cells induce metastasis-supporting neutrophil extracellular DNA traps.

Neutrophils, the most abundant type of leukocytes in blood, can form neutrophil extracellular traps (NETs). These are pathogen-trapping structures generated by expulsion of the neutrophil's DNA with associated proteolytic enzymes. NETs produced by infection can promote cancer metastasis. We show that metastatic breast cancer cells can induce neutrophils to form metastasis-supporting NETs in the absence of infection. Using intravital imaging, we observed NET-like structures around metastatic 4T1 cancer cells that had reached the lungs of mice. We also found NETs in clinical samples of triple-negative human breast cancer. The formation of NETs stimulated the invasion and migration of breast cancer cells in vitro. Inhibiting NET formation or digesting NETs with deoxyribonuclease I (DNase I) blocked these processes. Treatment with NET-digesting, DNase I-coated nanoparticles markedly reduced lung metastases in mice. Our data suggest that induction of NETs by cancer cells is a previously unidentified metastasis-promoting tumor-host interaction and a potential therapeutic target.

Establishment and characterization of bortezomib-resistant U266 cell line: constitutive activation of NF-κB-mediated cell signals and/or alterations of ubiquitylation-related genes reduce bortezomib-induced apoptosis.

Bortezomib has been known as the most promising anti-cancer drug for multiple myeloma (MM). However, recent studies reported that not all MM patients respond to bortezomib. To overcome such a stumbling-block, studies are needed to clarify the mechanisms of bortezomib resistance. In this study, we established a bortezomib-resistant cell line (U266/velR), and explored its biological characteristics. The U266/velR showed reduced sensitivity to bortezomib, and also showed crossresistance to the chemically unrelated drug thalidomide. U266/velR cells had a higher proportion of CD138 negative subpopulation, known as stem-like feature, compared to parental U266 cells. U266/velR showed relatively less inhibitory effect of prosurvival NF-κB signaling by bortezomib. Further analysis of RNA microarray identified genes related to ubiquitination that were differentially regulated in U266/velR. Moreover, the expression level of CD52 in U266 cells was associated with bortezomib response. Our findings provide the basis for developing therapeutic strategies in bortezomib-resistant relapsed and refractory MM patients.

TNF α mediated IL-6 secretion is regulated by JAK/STAT pathway but not by MEK phosphorylation and AKT phosphorylation in U266 multiple myeloma cells.

IL-6 and TNF α were significantly increased in the bone marrow aspirate samples of patients with active multiple myeloma (MM) compared to those of normal controls. Furthermore, MM patients with advanced aggressive disease had significantly higher levels of IL-6 and TNF α than those with MM in plateau phase. TNF α increased interleukin-6 (IL-6) production from MM cells. However, the detailed mechanisms involved in signaling pathways by which TNF α promotes IL-6 secretion from MM cells are largely unknown. In our study, we found that TNF α treatments induce MEK and AKT phosphorylation. TNF α -stimulated IL-6 production was abolished by inhibition of JAK2 and IKK ß or by small interfering RNA (siRNA) targeting TNF receptors (TNFR) but not by MEK, p38, and PI3K inhibitors. Also, TNF α increased phosphorylation of STAT3 (ser727) including c-Myc and cyclin D1. Three different types of JAK inhibitors decreased the activation of the previously mentioned pathways. In conclusion, blockage of JAK/STAT-mediated NF- κ B activation was highly effective in controlling the growth of MM cells and, consequently, an inhibitor of TNF α -mediated IL-6 secretion would be a potential new therapeutic agent for patients with multiple myeloma.

Imaging tumor-stroma interactions during chemotherapy reveals contributions of the microenvironment to resistance.

Little is known about the dynamics of cancer cell death in response to therapy in the tumor microenvironment. Intravital microscopy of chemotherapy-treated mouse mammary carcinomas allowed us to follow drug distribution, cell death, and tumor-stroma interactions. We observed associations between vascular leakage and response to doxorubicin, including improved response in matrix metalloproteinase-9 null mice that had increased vascular leakage. Furthermore, we observed CCR2-dependent infiltration of myeloid cells after treatment and that Ccr2 null host mice responded better to treatment with doxorubicin or cisplatin. These data show that the microenvironment contributes critically to drug response via regulation of vascular permeability and innate immune cell infiltration. Thus, live imaging can be used to gain insights into drug responses in situ.

RNA interference-directed caveolin-1 knockdown sensitizes SN12CPM6 cells to doxorubicin-induced apoptosis and reduces lung metastasis.

Human renal cell carcinoma (HRCC) is characterized by a high level of resistance to all treatment modalities. Therefore, the investigation of global gene expression in HRCC might help understand its biologic behavior and develop treatment strategies. Using cDNA microarray analysis, we initially compared gene expression profiles between HRCCs and adjacent normal tissues, and found that 87 were up-regulated and 127 genes were down-regulated. Next, a subset of genes, twofold differentially expressed, were validated by Northern blotting. Unexpectedly, caveolin-1, a gene reported to be a tumor suppressor gene, was found to be up-regulated in HRCC tissues. Expression level of caveolin-1 in SN12CPM6 (high metastatic clone) was higher than in SN12C (low metastatic clone), and SN12CPM6 was more resistant to doxorubicin (DXR) than SN12C. Caveolin-1 gene was slightly induced in surviving SN12C cells after DXR treatment. Furthermore, SN12CPM6-siCav1 cells, which were transfected with siRNA of cavelon-1 gene, were more sensitive to DXR, compared to SN12CPM6, but reduction of caveolin-1 gene expression did not affect tumor formation in subcapsule of kidney and lung metastasis. On the other hand, induction of caveolin-1 gene affected the production of lung metastasis under anti-cancer drug treatment: the incidence of pulmonary metastasis was significantly lower in SCID mice injected with SN12CPM6-siCav1 cells, and the number of pulmonary nodules decreased significantly (p = 0.0004). The above results together suggest that caveolin-1 may confer a growth advantage to cancer cells during DXR chemotherapy and surviving HRCC cells eventually might develop lung metastasis.

Establishment of a new Glivec-resistant chronic myeloid leukemia cell line, SNUCML-02, using an in vivo model.

OBJECTIVE: In this study, we report a newly established chronic myeloid leukemia (CML) cell line, SNUCML-02, which is resistant to imatinib and describe its biological characteristics. MATERIALS AND METHODS: Mononuclear cells were obtained from the bone marrow of a CML patient in blast crisis and were cultured in Dulbecco's modified Eagle's medium/F12 containing 20% fetal bovine serum. After 2 months of primary culture, these cells were injected into nonobese diabetic/severe combined immune-deficient mice via tail vein. Eight weeks after injection, mice were sacrificed and ex vivo culture was performed from the bone marrow cells isolated from the mice. The established cell line was named as SNUCML-02 and the biological features were characterized by cytogenetic analysis, fluorescence in situ hybridization, reverse transcriptase polymerase chain reaction, sequencing analysis, cell proliferation assay, and Western blot analysis. RESULTS: Cytogenetic studies using conventional G-banding and fluorescent in situ hybridization of SNUCML-02 demonstrated classical Philadelphia chromosome, (9;22)(q34;q11.2), and other abnormalities, such as add(11)(q23), +19 and +der(9;22). SNUCML-02 has the same BCR-ABL fusion transcript as was seen in K562 cells, but has no mutations in the ABL kinase domain. SNUCML-02 was more resistant to imatinib (STI571, Gleevec, Glivec) than other CML cell lines (K562, Kcl22, and BV173). SNUCML-02 has constitutive activation of extracellular signal-regulated kinase phosphorylation. In addition, interleukin-3 induced c-ABL phosphorylation and constitutively enhanced extracellular signal-regulated kinase phosphorylation was not inhibited by imatinib in SNUCML-02. CONCLUSION: SNUCML-02 is a new established cell line with a relatively high level of resistance to imatinib, which is useful for investigating the pathogenesis of CML progression, and will be useful in developing optimal therapeutic strategies for this ailment.

Molecular characterization and prognostic significance of FLT3 in CML progression.

To characterize the molecular mechanisms involved in the transition from the chronic phase to blast crisis in chronic myelogenous leukemia (CML), gene expression profiles of leukemic cells from patients in the chronic and blast crisis phases were analyzed using an 8.7K cDNA chip and real-time PCR. A transient transfection analysis was conducted to evaluate the role of FLT3, which was significantly upregulated in the blast crisis patients. Abl and c-Kit induction was detected in K562 cells transfected with FLT3 cDNA (K562/FLT3), and Abl and c-Kit levels were reduced in K562/FLT3 cells transfected with FLT3-siRNA (K562/FLT3-siRNA). The induction of FLT3 in CML cells attenuated imatinib-induced apoptosis. The opposite effect was observed in K562/FLT3-siRNA cells. An increased level of cleaved PARP and decreased level of pro-caspase 3 were noted when K562/FLT3-siRNA cells were treated with imatinib. These findings indicate that FLT3 is associated with disease progression, despite imatinib therapy. These results may help in the prediction of disease progression in CML patients and the development of more appropriate therapeutic modalities.

Non-A type nucleophosmin 1 gene mutation predicts poor clinical outcome in de novo adult acute myeloid leukemia: differential clinical importance of NPM1 mutation according to subtype.

Mutations of nucleophosmin gene (NPM1) are known to be related to good prognosis in AML patients lacking FLT3 internal tandem duplication (FLT3-ITD). Recently, NPM1 mutations other than type A were reported, but their clinical significance is not well known. Retrospective medical record review of 106 de novo AML patients lacking FLT3-ITD, who received induction chemotherapy from three centers in Korea between 1997 and 2007, was performed. Direct sequencing of NPM1 and RT-PCR for FLT3-ITD was performed on genomic DNA derived from blood samples of patients before induction chemotherapy for detection of mutations. NPM1 mutation was detected in 18 patients, where 13 were type A mutants and 5 were non-type A mutants. CR, CR1-D and OS was not different according to NPM1 mutational status overall. But, non-type A NPM1 mutation was related to shorter CR1-D when compared with NPM1 wild types and NPM1 type A mutation (p = 0.004). OS was shorter in non-type A mutants when compared with NPM1 wild-type patients and NPM1 type A mutants (p = 0.001). The type of mutation of NPM1 is important for prognosis in de novo AML lacking FLT3-ITD. Non-A type NPM1 mutation is a poor prognostic factor.

Different clinical importance of FLT3 internal tandem duplications in AML according to FAB classification: possible existence of distinct leukemogenesis involving monocyte differentiation pathway.

Impact of FLT3 receptor tyrosine kinase activation via internal tandem duplication (ITD) of the juxtamembrane region on outcome of acute myeloid leukemia (AML) is still controversial. Recent researches reveal a role of FLT3 in monocyte differentiation in hematopoiesis. We analyzed the clinical impact of FLT3 alterations in adult AML patients excluding acute promyelocytic leukemia (APL) who received induction chemotherapy according to morphologic classification. Retrospective review of medical records from three centers in Korea between 1997 and 2007 was performed. Polymerase chain reaction was performed on genomic DNA derived from blood samples of patients before induction chemotherapy for FLT3-ITD detection. We assessed overall survival (OS), first disease-free survival (1-DFS), and response to induction chemotherapy. One hundred eighty-four patients (median age 49.1 years, range 16.0-76.5) with AML excluding APL received induction chemotherapy from three centers. FLT3-ITD was detected in 22 patients. One hundred forty-one patients were below age 60. One hundred seventy-nine patients received induction chemotherapy with cytarabine and idarubicin (AId) regimen. One hundred nineteen patients achieved complete remission (CR) after first induction chemotherapy. FLT3-ITD was not related to achievement of CR. 1-DFS was longer in patients without FLT3-ITD (median 1-DFS 16.5 vs. 8.5 months, p = 0.025). 1-DFS was not different according to FLT3-ITD status in nonmonocyte lineage leukemia (p = 0.355), while 1-DFS was shorter in monocyte lineage leukemia for FLT3-ITD positive patients (20.9 vs. 2.4 months, p < 0.001). FLT3-ITD had no impact on OS except for monocyte lineage, where OS was significantly shorter in FLT3-ITD positive group (39.4 vs. 6.0 months, p = 0.026). Moreover FLT3-ITD was stronger prognostic factors in monocyte lineage AML than risk stratification based on cytogenetics. Status of FLT3-ITD should be analyzed differently in AML patients according to morphologic profile. FLT3-ITD is a predictive and prognostic marker only in monocyte lineage patients. This result suggests an existence of distinct subset of monocyte lineage AML with leukemogenesis involving FLT3 activating pathway.

Blockage of interleukin-6 signaling with 6-amino-4-quinazoline synergistically induces the inhibitory effect of bortezomib in human U266 cells.

The transcription factor nuclear factor-kappa B (NF-kappaB) regulates the transcription of a number of genes involved in a variety of cellular responses, including cell survival, inflammation, and differentiation. NF-kappaB is activated by a variety of stimuli, proinflammatory cytokines, mitogens, growth factors, and stress-inducing agents. Aberrant NF-kappaB expression is considered to be one of the oncogenic factors of cancer and the constitutive activation of NF-kappaB is observed in several hematologic disorders [classic Hodgkin's lymphoma, diffuse large B cell lymphoma, and multiple myeloma (MM)], and the modulation of NF-kappaB activation is emerging as a promising novel anticancer therapeutic strategy.Therefore, we focused on the regulation of NF-kappaB activation in MM. When U266 cells were treated with 6-amino-4-quinazoline, an NF-kappaB activation inhibitor, we determined that it most effectively blocked the interleukin (IL)-6-induced activation of MAPK and JAK/STAT pathways among different signaling inhibitors. The results of the luciferase assay indicated that 6-amino-4-quinazoline inhibited NF-kappaB activation with diminished NF-kappaB protein bound to NF-kappaB DNA binding sites. In addition, 6-amino-4-quinazoline suppressed the production of IL-6, which affected MM cell proliferation. Furthermore, combined treatment with bortezomib and 6-amino-4-quinazoline effectively inhibited the IL-6 and soluble IL-6R-induced activation of STAT3 and extracellular signal-regulated kinase phosphorylation. Our data showed that the inhibition of NF-kappaB activation abrogated MM cell proliferation induced by the IL-6 pathway, and might represent a promising therapeutic strategy for the treatment of MM.

Curcumin in combination with bortezomib synergistically induced apoptosis in human multiple myeloma U266 cells.

Growth of multiple myeloma cells is controlled by various factors derived from host bone marrow microenvironments. Interaction between multiple myeloma cells and bone marrow stromal cells (BMSCs) plays an important role in the expression of adhesive molecules and secretion of growth factors involved in multiple myeloma (MM) cell growth, survival, and resistance to anticancer drugs. Recently, the possibility of developing novel anti-cancer therapeutic strategies targeting both MM cells and MM cell-BMSC interactions has been discussed. Here we present data showing that curcumin, a major constituent of turmeric compounds extracted from the rhizomes of the plant Curcuma longa, effectively reduced the growth of MM cells and BMSCs. Upon treatment with curcumin, IL-6/sIL-6R-induced STAT3 and Erk phosphorylation was dramatically reduced in the co-cultured cells. In addition, curcumin inhibited the production of pro-inflammatory cytokines and VEGF, factors that are associated with the progression of multiple myeloma, from both MM cells and BMSCs. In a combination treatment with curcumin and bortezomib, IL-6/sIL-6R-induced STAT3 and Erk phosphorylation was effectively inhibited. Moreover, this combination treatment synergistically inhibited the growth of MM cells co-cultured with BMSCs as compared to controls. Taken together, these results indicate that curcumin potentiates the therapeutic efficacy of bortezomib in MM suggesting this combination therapy to be of value in the clinical management of MM.

Combination of SK-7041, one of novel histone deacetylase inhibitors, and STI571-induced synergistic apoptosis in chronic myeloid leukemia.

Although STI571 still plays a key role in the treatment of chronic myeloid leukemia, emergence of resistance to STI571 is a major obstacle to successful outcome. Therefore, new agents that increase the sensitivity of chronic myeloid leukemia cells to STI571 are urgently required. SK-7041 is a novel hybrid synthetic histone deacetylase inhibitor derived from the hydroxamic acid of trichostatin A and pyridyl ring of MS-275. Its cytotoxic effects were examined both as a single agent and in combination with STI571 in acute and chronic myeloid leukemia. SK-7041 exhibited growth inhibition of leukemia cells by downregulation of CDK4, cyclin E and cyclin B1 expression, and by upregulation of p21 expression with subsequent activation of the mitochondria-mediated caspase pathway. SK-7041 showed synergism on growth inhibition, cell cycle arrest and induction of apoptosis in chronic myeloid leukemia (K562) when combined with STI571. The synergistic effect was mediated through the same mechanism as in SK-7041 alone, involving reduction of cyclin D1 and induction of p21. Taken together, our findings suggest that SK-7041 is active against leukemia and offers new prospects for overcoming STI571 resistance in chronic myeloid leukemia.