Anticancer research最新文献

Background/aim: Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma worldwide. Patients can have a wide range of clinical features and behavior which does not necessarily correlate to histologic grade or Ki-67 proliferation index. We hypothesized that patients with low grade but high proliferative index (LG/HP) FL have a more aggressive disease course. The aim of this study was to determine the role of LG/HP on the outcomes of FL patients.

Patients and methods: A retrospective single center study of FL patients treated within the Allegheny Health Network was conducted from January 2011 to December 2021. Patients were divided into three groups: low grade/high proliferation index (PI) (LG/HP), low grade/low PI (LG/LP), and high grade (HG). Cox regression models looking at variables including age, sex, race, Ann Arbor staging, PET SUV_max, FLIPI score, and treatment details were used to analyze predictors of progression. Survival estimates were calculated using the Kaplan-Meier method and compared using the Log-rank test.

Results: A total of 145 patients were treated for FL during the study period. Most were males and fell into the LG/LP group. We determined that the median progression-free survival in the LG/HP group was numerically worse than the LG/LP group; however, this did not meet statistical significance.

Conclusion: Our data suggest that a different treatment approach may not be warranted for LG/HP FL patients.

Background/aim: Hederagenin (3β,4α-3,23-dihydroxyolean-12-en-28-oic acid) is a natural pentacyclic triterpene that is present in various medicinal plants and exhibits pharmacological activities against various diseases, including cancer. The aim of the study was to investigate the effect of Aq3639 (3β-[(O-α-L-rhamnopyranosyl-(1→2)-α-L-arabinopyranosyl)oxy]olean-12-en-28-oic acid), a hederagenin glycoside comprising hederagenin and a disaccharide of L-rhamnose and L-arabinose, on breast cancer cells.

Materials and methods: Aq3639 was isolated from the pericarps of Akebia quinata fruits, and its effects on cells from the human breast cell line MCF-7 were examined.

Results: Aq3639 was found to markedly inhibit the proliferation of MCF-7 cells in a concentration-dependent manner (particularly at concentrations above 25 μmol/l). The inhibitory effect [half-maximal inhibitory concentration (IC₅₀)=13.10 μmol/l] was similar to that of tamoxifen, which is used as a therapeutic agent for estrogen receptor-positive breast cancer; the inhibitory effect was also approximately seven-times greater than that of hederagenin (IC₅₀=93.05 μmol/l). Interestingly, neither of the sugars present in Aq3639, L-rhamnose nor L-arabinose, affected cell inhibition. Additionally, Aq3639 increased the generation of reactive oxygen species and, consequently, induced apoptosis in the MCF-7 cells in a time-dependent manner.

Conclusion: Our results strongly suggest that Aq3639 may be useful in the prevention and treatment of breast cancer.

Background/aim: Solute carrier (SLC) family 15 member 2 (SLC15A2) is an integral member of the SLC family that plays a pivotal role in numerous biological processes, including the regulation of cellular signaling pathways. However, its role in prostate cancer (PCa) remains inadequately elucidated. This study aims to investigate the prognostic significance of SLC15A2 in PCa.

Materials and methods: We evaluated the expression levels and prognostic significance of SLC15A2 in multicenter cohorts of PCa through differential expression analysis, survival analysis, and Cox regression. These findings were validated through immunohistochemistry and in vitro experiments. Gene set enrichment analysis, mutation analysis, and methylation analysis were used to investigate the potential biological functions of SLC15A2. Finally, drug target prediction analysis was conducted to identify small molecule therapeutic agents specifically targeting SLC15A2 in PCa.

Results: The expression level of SLC15A2 in PCa tissues was significantly lower compared to benign tissues, and reduced expression of SLC15A2 was often associated with early biochemical recurrence (BCR) and decreased overall survival in PCa patients. Moreover, results from in vitro experiments indicated that knockdown of SLC15A2 markedly enhanced the proliferation and migratory capacity of PCa cells. Enrichment analysis indicated that SLC15A2 predominantly activates pathways related to cell proliferation, adhesion, and lipid metabolism while inhibiting pathways associated with protein synthesis, degradation, RNA metabolism, and energy metabolism. Notably, the frequency of TP53 mutations and 8q24.21 copy number variations was significantly higher in the low SLC15A2 expression group. DNA hypermethylation of SLC15A2 at gene body linked to downregulation of SLC15A2 in PCa. Finally, analysis with the Connectivity Map database identified several promising small molecule drugs for PCa treatment, including rucaparib.

Conclusion: Our findings suggest that SLC15A2 serves as a promising prognostic biomarker in PCa, enabling accurate risk stratification for BCR. This insight may contribute to the advancement of personalized treatment strategies for PCa.

Background/aim: Chemotherapy based on 5-fluorouracil (5-Fu) is the first-line treatment for advanced gastric cancer (GC) patients. Importantly, 5-Fu resistance is recognized as a major obstacle for the successful treatment of GC. Circular RNAs (circRNAs) are non-coding RNAs involved in the pathogenesis of GC. However, their role in the mechanism of 5-Fu resistance in GC remains largely unknown. The purpose of this study was to explore and elucidate the biological function and molecular mechanism of circRNAs underlying 5-Fu resistance in GC.

Materials and methods: High-throughput sequencing results for intersection analysis were used to select a novel differentially expressed circRNA hsa_circ_0004650. The expression levels of the new circRNA between 5-Fu-sensitive and 5-Fu-resistant GC cells were evaluated using quantitative real-time polymerase chain reaction (qRT-PCR), and biological behaviors, such as proliferation and apoptosis of GC cells, were observed after silencing the hsa_circ_0004650. The mechanism of hsa_circ_0004650 sponges miR-145-5p to regulate 5-Fu resistance in GC cells was investigated by luciferase reporter assay, qRT-PCR, CCK-8 assay, Calcein AM/PI double fluorescence staining and flow cytometry.

Results: hsa_circ_0004650 was identified as a differentially expressed circRNA between 5-Fu-sensitive GC and 5-Fu-resistant GC cells. Hsa_circ_0004650 was up-regulated in 5-Fu-resistant GC cells. Silencing of hsa_circ_0004650 in 5-Fu-resistant GC cells, the survival rates of cells treated with increasing doses of 5-Fu for 24 h and 48 h were decreased (p<0.01); the mortality rates of SGC-7901-5-Fu cells were increased (17.86%±0.6 vs. 44.86%±1.52; p<0.001), and those of BGC-823-5-Fu cells were increased (8.17%±7.80 vs. 26.61%±1.12; p<0.001); and the apoptosis rates of cells treated with the same concentration of 5-Fu were increased (p<0.001). Mechanistically, miR-145-5p was confirmed as a downstream target of hsa_circ_0004650. By the down-regulation of the expression of miR-145-5p in 5-Fu-resistant GC cells, the survival rates of cells treated with increasing doses of 5-Fu for 24 h and 48 h were increased (p<0.05); the mortality rates of SGC-7901-5-Fu cells were decreased (12.86%±1.10 vs. 7.83%±0.53; p<0.01), those of BGC-823-5-Fu cells were decreased as well (16.99%±1.31 vs. 11.40%±0.72; p<0.01); and the apoptosis rates of cells treated with the same concentration of 5-Fu were decreased (p<0.001).

Conclusion: The circRNA hsa_circ_0004650 promotes chemotherapy resistance to 5-Fu in GC cells through sponge adsorption of miR-145-5p, which offers a potential approach to overcome 5-Fu resistance in GC.

Background/aim: CXCR3B has been positively involved in the inhibition of cancer and angiogenesis. The present study investigated the role of CXCR3B in a cell model of hepatocellular carcinoma, SK-Hep1.

Materials and methods: The blockade of CXCR3B expression in SK-Hep1 was investigated in terms of cell viability, cell cycle, and cell apoptosis using MTT assay and flow cytometry. In addition, the effect of blocking CXCR3B expression on cell migration and invasion was examined using scratch motility, transwell migration, and invasion assays. Furthermore, the cytotoxic effect of NK-92 cells against CXCR3B blocked SK-Hep1 was analyzed using the CytoTox96 assay, and the expression of NKp30⁺, NKG2D⁺, and NKG2C⁺ on NK-92 cells in a co-culture with SK-Hep1 was measured using flow cytometry.

Results: Blocking CXCR3B expression had no effect on the viability, cell cycle or apoptosis of SK-Hep1 cells. However, blockade of CXCR3B expression significantly increased the migratory and invasive ability of SK-Hep1 along with increased protein expression of slug, vimentin, and N-cadherin. CXCR3B blockade reduced the cytotoxicity of NK-92 against SK-Hep1 and inhibited the expression of activating receptors, NKp30⁺, NKG2D⁺, and NKG2C⁺ in NK-92 cells.

Conclusion: CXCR3B may play a positive role in suppressing HCC by attenuating natural killer cell cytotoxicity against HCC.

Background/aim: Plexiform neurofibromas are the hallmark of neurofibromatosis type 1, an autosomal dominantly inherited multisystem disorder. Spinal plexiform neurofibromas can particularly cause severe neurological symptoms. Treatment options are limited due to invasive growth, and targeted therapy with selumetinib is only approved for inoperable tumors in children. The aim of this report was to highlight that selumetinib therapy post-surgery provides an alternative strategy for spinal plexiform neurofibroma, providing both an immediate relief of the symptoms and long-term tumor management.

Case report: We describe a patient with neurofibromatosis type 1 and a large spinal plexiform neurofibroma causing severe neurological deficits. A drastic clinical improvement was achieved 6 months after neurosurgical spinal decompression and adjuvant selumetinib therapy.

Conclusion: A combination of decompression surgery and selumetinib therapy provides a promising option for the management of spinal plexiform neurofibromas causing severe neurological deficits.

Background/aim: Extracellular signal-regulated kinases (ERK)1/2 are important regulatory proteins that control cell proliferation and survival, playing a significant role in cancer progression, metastasis, and chemoresistance. This study investigated the effects of ERK1/2 inhibitors on the in vitro growth of acute leukemia cell lines.

Materials and methods: Three ERK1/2 inhibitors were used: SCH772984, temuterkib (LY3214996), and ulixertinib (BVD-523). Four acute myeloid leukemia cell lines (OCI/AML3, HL-60, THP-1, and U-937) and two T-lymphoblastic leukemia cell lines (Jurakt and KOPT-K1) were treated with these inhibitors. Cell growth was assessed using a colorimetric assay, and cell-cycle progression and apoptosis were analyzed using flow cytometry. The expression of intracellular signaling proteins was evaluated via immunoblotting. The effects of small interfering RNA (siRNA)-mediated ERK1/2 knockdown were also evaluated.

Results: The inhibitors suppressed the growth of three leukemia cell lines (OCI/AML3, HL-60, and THP-1) harboring neuroblastoma rat sarcoma virus (NRAS) mutations. Growth suppression occurred through G0/G1 arrest in all three cell lines and through apoptosis in OCI/AML3 cells. Immunoblotting demonstrated that these inhibitors suppressed the expression of MYC proto-oncogene, bHLH transcription factor (MYC), in the three cell lines. The additional molecular mechanisms of growth suppression varied depending on the specific inhibitor and cell line. The inhibitors had milder suppressive effects on normal lymphocytes compared to the leukemia cell lines.

Conclusion: ERK1/2 inhibitors may serve as novel molecular-targeted drugs for treating leukemia with NRAS mutations.

Background/aim: Stem-like cancer cells are believed to be the leading cause of therapy resistance in malignant melanoma (MM). All-trans retinoic acid (ATRA) differentiation therapy is considered a promising approach to eradicate stem-like cancer cells, but some melanoma cells are resistant to ATRA. This study aimed to examine whether resveratrol (RS), a natural polyphenol compound, could improve the response of MM stem-like cells to ATRA and explore the possible underlying mechanisms.

Materials and methods: MM stem-like cells were established from a spheroid model of A375 human MM cell line. The response to RES alone and in combination with ATRA, was examined through analysis of cancer stemness, cell viability, and protein expression.

Results: The stem-like cells showed resistance to the anticancer drug docetaxel; however, the combination of RES and ATRA augmented the effects of docetaxel. Accordingly, these combinatorial effects were associated with significant inhibition of the expression levels of stemness markers CD133, OCT4, CD271, and ABCG2. The tested combinations also led to a significant increase in melanocyte differentiation marker SOX9, while efficiently suppressing the dedifferentiation marker SOX10. Notably, RES alone effectively up-regulated retinoic acid receptor beta (RARβ) expression and down-regulated crucial mediators like DNMT1, polycomb-group proteins EZH2, and BMI-1, which mechanistically explain how RES enhanced the differentiation-inducing effects of ATRA.

Conclusion: The resistance of MM stem-like cells to ATRA can be attenuated by RES and combined applications of ATRA and RES provide a promising strategy for MM treatment.

Background/aim: Many patients with non-small cell lung cancer (NSCLC) receive palliative radiotherapy (RT). Several factors were analyzed to aid in prescribing an optimal treatment for these patients.

Patients and methods: This prospective observational multicenter study investigated several potential factors for associations with overall survival (OS) in 61 patients with NSCLC receiving palliative RT with or without chemotherapy (CT). Investigated factors included age, sex, performance status, history of smoking or alcohol, hemoglobin, co-morbidities, different clinical symptoms, and quality-of-life aspects.

Results: Median OS was 10.8 months, and OS rates at 6, 12, and 24 months were 58.5%, 42.5%, and 28.4%, respectively. On multivariate analysis, RT alone (without CT), RT doses ≤30 Gy, advanced tumor stage (stage IV), and poor emotional functioning at diagnosis were associated with significantly worse OS.

Conclusion: Patients with NSCLC assigned to palliative RT may benefit from RT doses >30 Gy and additional CT. Sequential CT appears preferable, since concurrent CT increases esophageal toxicity.

Background/aim: A new index, inflammation-nutrition biomarker score (INS), based on host factors, including lymphocyte to C-reactive protein ratio, C-reactive protein to albumin ratio, advanced lung cancer inflammation index, and nutritional risk index, correlated with post-operative survival time independent of the tumor, node, metastasis (TNM) stage, in a cohort of patients with various types of malignancies. Therefore, this study aimed to evaluate the prognostic value of INS in patients with colorectal cancer who underwent curative resection.

Patients and methods: We retrospectively evaluated 476 consecutive patients who underwent curative surgery for stage I-III colorectal cancer.

Results: Based on the INS definition, 240, 132, 57, 23, and 24 patients had a score of 0, 1, 2, 3, and 4, respectively. Patients with INS of 0 and 1 were classified into the low-INS group, and those with INS of 2, 3, and 4 were classified into the high-INS group. The relapse-free and overall survival rates were significantly worse in the high-INS group than in the low-INS group. Furthermore, multivariate analysis of the prognostic factors indicated that INS is an independent prognostic factor for poor relapse-free and overall survival.

Conclusion: The combined evaluation of INS and TNM stages may allow for more accurate prognostication.