Anticancer research最新文献

Background/aim: Metastatic breast cancer remains a major clinical challenge despite the availability of various chemotherapeutic agents. Current metabolic inhibitors have limitations, prompting the need for innovative strategies that selectively target tumor cells while sparing normal tissues. This study aimed to propose a novel approach focused on depriving tumor cells of glucose while ensuring nutrient delivery to normal cells.

Materials and methods: A comprehensive literature review was conducted using PubMed and Google Scholar. The proposed strategy involved focusing on studies that deplete glycogen stores in normal tissues through prolonged fasting, followed by administration of total parenteral nutrition (TPN) enriched with essential ingredients encapsulated in specialized liposomes. Three liposomal strategies were outlined: 1-pH-sensitive copolymer coating: liposomes coated with polyethylene glycol-poly-L-histidine (PEG-PLH) selectively release contents in normal tissues by binding glucose transporters (GLUTs) while avoiding tumor cell GLUTs. 2-Superhydrophobic fluorinated compounds: conjugation with trastuzumab targets HER2 ligands on tumor cells, preventing liposome accumulation in tumors. 3-Superhydrophobic Zwitterionic modifications: these create a hydration layer around liposomes, preventing passage through capillary walls and reducing tumor tissue accumulation.

Results: The strategies were designed to selectively reduce glucose availability to tumor cells while preserving normal cellular metabolism. The proposed liposomal modifications theoretically enhance targeted delivery and minimize off-target effects, providing a novel framework for metabolic therapy in metastatic breast cancer.

Conclusion: This novel glucose-targeted liposomal approach shows potential to improve therapeutic specificity and efficacy in metastatic breast cancer. Further in vitro, in vivo, and clinical studies are warranted to validate its effectiveness and explore applicability to other solid tumors.

Background/aim: Inferior vena cava (IVC) leiomyosarcoma is a rare malignant tumor, with fewer than 500 cases described in literature. Prognosis is poor, and radical surgical resection remains the gold standard of treatment. However, the optimal surgical technique is a subject of ongoing debate.

Patients and methods: From October 1993 to December 2024, 33 patients (23 females, 10 males; median age 52.2 years) underwent surgical resection of IVC leiomyosarcoma with vascular reconstruction using a polytetrafluoroethylene (PTFE) graft. A multidisciplinary team evaluated all patients. The surgical procedure involved en bloc resection of the tumor with a minimum 1 cm healthy margin. The reconstruction was cavo-caval, cavo-bi-iliac, cavo-caval with right renal vein resection and right nephrectomy and cavo-caval with left renal vein resection and reimplantation. Study's primary endpoints were overall survival, disease-free survival and graft patency. Secondary endpoints were intraoperative and postoperative complications.

Results: No 30-day postoperative mortality was observed. Five- and 10-year survival rates were 57.7% and 15.2%, respectively. Five- and 10-year disease-free survival rates were 36.4% and 18.2%, respectively. Graft thrombosis was observed in 13 patients (39.4%). Median follow-up was 48 months (range=12-120 months; IQR=24.0-68.5). No cases of prosthetic infection or acute graft thrombosis were observed in this series. Postoperative complications included acute kidney injury (AKI) in four patients (12.1%), respiratory distress in two patients (6.1%) distress and postoperative bleeding in three patients (9.1%).

Conclusion: Type I and II IVC leiomyosarcomas resection with subsequent PTFE vascular reconstruction is safe, with a low rate of disease-free survival and a risk of graft thrombosis at medium follow-up.

Background/aim: The prognostic impact of the timing of adjuvant chemotherapy initiation in patients with resected pancreatic cancer is unclear. Therefore, this study aimed to investigate whether delayed initiation of S-1 adjuvant chemotherapy affects the survival of patients with resectable pancreatic cancer.

Patients and methods: Patients who received S-1 adjuvant chemotherapy after undergoing R0/R1 resection were grouped according to whether adjuvant chemotherapy was initiated <60 (n=36) or ≥60 days (n=27) after surgery. Correlations between the time to chemotherapy initiation, clinicopathological factors, and survival were analyzed.

Results: The median and mean times to chemotherapy initiation were 58 and 61 days, respectively. The delayed group had worse 2-year overall (57% vs. 80%, p=0.032) and recurrence-free survival (35% vs. 54%, p=0.044) rates than the early group. These results were similar in patients who completed S-1 adjuvant chemotherapy. In multivariate analysis, delayed initiation of chemotherapy, R1 resection, and tumor size (≥40 mm) were independent prognostic factors for poor overall survival. The delayed group had more patients with severe postoperative complications (Clavien-Dindo grade ≥III) (30% vs. 8%, p=0.028) and delayed recovery of serum albumin levels (postoperative days 7, 14, and 30: p=0.040, 0.004, and 0.003, respectively) than the early group.

Conclusion: Delayed initiation of S-1 adjuvant chemotherapy had an adverse impact on survival and was correlated with severe postoperative complications and delayed recovery of postoperative nutritional status.

Background/aim: Ampulla of Vater carcinoma is a rare malignancy with limited survival after resection, and the role of adjuvant therapy remains unclear. S-1 (oral prodrug of 5-FU with modulators gimeracil and oteracil) has been adopted as an adjuvant treatment for biliary cancers in Japan, but its benefit in ampullary carcinoma is uncertain. We aimed to identify prognostic factors and evaluate the impact of adjuvant S-1 in resected ampullary carcinoma.

Patients and methods: We retrospectively reviewed 53 patients who underwent pancreatoduodenectomy for ampullary carcinoma at a single institution (2005-2023). Clinicopathologic data and use of adjuvant S-1 were collected. Cancer-specific survival (CSS) and relapse-free survival (RFS) were estimated by the Kaplan-Meier method and compared by the log-rank test. Cox proportional hazards models identified independent prognostic factors. Outcomes with versus without adjuvant S-1 were compared within the node-positive (N+) subset of patients.

Results: The 5-year CSS and RFS for all patients were 70.8% and 66.2%, respectively. On multivariate analysis, lymph node metastasis (N+) was the only independent predictor of worse CSS (p=0.04) and RFS (p=0.001). Among N+ patients (n=20), 5-year CSS (51.4% vs. not reached) and RFS (18.0% vs. 18.7%) were similar with adjuvant S-1 (n=11) or surgery alone (n=9) (p=0.5 and 0.4). Adjuvant S-1 did not improve survival in node-positive patients.

Conclusion: Lymph node status is a major prognostic factor in ampullary carcinoma. Adjuvant S-1 chemotherapy conferred no significant survival benefit for node-positive patients, underscoring the need for more effective adjuvant strategies.

Background/aim: Afatinib is an irreversible EGFR-TKI effective against uncommon EGFR mutations in non-small cell lung cancer (NSCLC), but the influence of mutation subtype and starting dose on treatment outcomes remains unclear. This study aimed to evaluate the clinical outcomes of patients with uncommon EGFR-mutated NSCLC treated with afatinib, focusing on whether a reduced starting dose (30 mg) provides comparable efficacy and tolerability to the standard 40 mg dose. Additionally, we sought to explore the potential impact of specific uncommon EGFR mutation subtypes on treatment response.

Patients and methods: We retrospectively analyzed patients with stage IV NSCLC harboring uncommon EGFR mutations who received afatinib 30 mg or 40 mg daily at two university affiliated hospitals. Mutations were categorized as single uncommon, compound (rare + common), or double rare (rare + rare). Clinical characteristics, treatment response, and survival outcomes were compared between mutation subgroups and dosing cohorts. Progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan-Meier analysis and compared with the log-rank test.

Results: A total of 46 patients were included (30 mg: n=28; 40 mg: n=18). The objective response rate was 71.7%, and disease control rate 93.5%. Patients with double-rare mutations had significantly longer survival than those with single uncommon mutations (median PFS 37.1 vs. 12.3 months, p=0.01; median OS 63.7 vs. 19.6 months, p=0.042). In the 30 mg group, this benefit was more pronounced (PFS p=0.0039; OS p=0.0287), whereas survival differences by mutation subtype were not significant in the 40 mg cohort. Treatment was well tolerated, with fewer grade ≥3 adverse events in the 30 mg group.

Conclusion: Afatinib 30 mg daily achieved comparable efficacy and better tolerability than 40 mg, with significantly longer PFS and OS in patients harboring compound or double-rare EGFR mutations. These findings suggest that lower-dose afatinib may optimize efficacy and safety in patients with uncommon EGFR-mutant NSCLC.

Background/aim: Treatment of cancers known to be positive for the nuclear progesterone receptor (nPR), e.g., breast, ovarian, and endometrial cancers with PR modulators/antagonists, e.g., mifepristone, have not shown impressive improvement in palliative or longevity benefits. In contrast, several case reports showed considerable palliation and/or extension of life using mifepristone treatment for various advanced cancers devoid of the nPR. The aim of this study was to determine whether mifepristone therapy could provide improved quality of life in a patient with breast cancer considered terminal based on extensive brain and lung metastases in which the estrogen receptor (ER) was present in 99% of the cells but only 1% positive for the nPR.

Case report: A 64-year-old woman with stage IV breast cancer with very symptomatic brain and lung metastases who was considered terminal was first treated with letrozole. She failed to show any clinical improvement. Attempts to also treat her with abemaciclib and subsequently ribociclib were stopped after a very short course related to side effects. Mifepristone 200 mg daily tablets resulted in marked improvement in her fatigue, dyspnea on exertion, cognition, and her issues with balance. This was associated with a 75% reduction in the size of the lung lesions and no new metastatic lesions by position emission tomography two months after starting mifepristone. She lived eight months and still maintained good quality of life, but she died of a cerebral vascular accident.

Conclusion: Mifepristone provided marked palliative benefit in this patient with nPR-negative, metastatic breast cancer, suggesting potential therapeutic value in similar cases. Confirmation of efficacy will require larger studies focused on tumors with absent or minimal nuclear progesterone receptor expression.

Background/aim: Small molecule anti-cancer drugs can cause adverse effects; most commonly low blood cell counts. Protein kinase D2 (PKD2) is highly expressed in neutrophils, and this study investigated the role of PKD2 inhibition on the survival of human neutrophils using small molecule compounds.

Materials and methods: The kinase inhibition profiles of two Polo like kinase 1 (PLK1) inhibitors, TAK-960 derivative and Compound A were evaluated using 265 kinase enzyme assays. HL60 cells were differentiated into neutrophil-like cells, followed by siRNA-mediated knockdown of PKD2, and cell viability was assessed. Compounds were tested for their effects on cell viability in differentiated HL60 cells and human neutrophils isolated from healthy donors. Furthermore, correlation between PKD2 inhibition and peripheral white blood cell counts was assessed for 23 difluoropyrimido-diazepinone compounds in nude mice bearing HT-29 human colon cancer cell xenografts.

Results: PKD2 knockdown resulted in reduced cell viability in differentiated HL60 cells. Compound A, which selectively inhibits PKD2, significantly reduced the viability of differentiated HL60 cells and human neutrophils, to a greater extent than TAK-960. In contrast, suppression of PLK3, which is also highly expressed in neutrophils, did not affect cell viability, indicating that PKD2 is critical for neutrophil survival. Moreover, a significant positive correlation was observed between PKD2 inhibition and white blood cell counts in nude mice (Pearson's correlation, r=0.75, p=0.009).

Conclusion: PKD2 plays a crucial role in human neutrophil survival. Minimizing PKD2 inhibition during small-molecule drug design could be essential to reduce the risk of neutropenia in patients under anti-cancer treatment.

Recent advances in cancer biology have revolutionized the development of targeted and combination therapies, offering new avenues for improving cancer management. Among the central molecular regulators, the mammalian target of rapamycin (mTOR) plays a pivotal role in orchestrating cell growth, metabolism, and survival. Aberrant activation of mTOR signaling driven by genetic mutations or dysregulation of upstream pathways such as phosphoinositide 3-kinase (PI3K)/AKT has been strongly implicated in cancer progression, metastasis, and therapeutic resistance. Consequently, mTOR has emerged as a promising target for anticancer drug development. Although synthetic mTOR inhibitors, including rapamycin and its analogs (rapalogs), have shown clinical benefits, their limited efficacy and the emergence of resistance have highlighted the need for novel strategies. Natural product-derived mTOR modulators have gained increasing attention due to their multi-targeted mechanisms of action, simultaneously modulating mTOR and its upstream or parallel signaling networks. These compounds exhibit potent anticancer properties, including suppression of tumor growth, induction of apoptosis, and reversal of drug resistance. This review elucidates the biological functions of mTOR in tumorigenesis and delineates its regulatory mechanisms underlying malignant phenotypes. Furthermore, it emphasizes the therapeutic promise of natural products as a rich source of mTOR inhibitors, providing insights for the rational design of innovative cancer therapies and combination regimens.

Background/aim: Coumarins (Benzopyran-2-one) are a broad class of compounds of both natural and synthetic origin with diverse pharmacological properties that have attracted intense interest in recent years. For example, the coumarin nucleus has emerged as a promising scaffold for monoamine oxidase (MAO) inhibitors (MAOIs), an essential target for developing drugs to treat neurodegenerative disorders. In the present study, we report the in vitro cytotoxic and MAO inhibitory activities of 3-acylcoumarin-oximes (7a-l) bearing various substituent groups on the core coumarin ring.

Materials and methods: The cytotoxic activity was evaluated using crystal violet dye binding, MAO activity was assayed using the MAO-GloTM kit, and the Free radical scavenging activities of the most active compound were tested spectrophotometrically using 2,2-diphenyl-1-picrylhydrazyl radical (DPPH) and hydrogen peroxide (H₂O₂) methods.

Results: The in vitro cytotoxic activity indicated that all the synthesized compounds were non-cytotoxic against Neuroblastoma 2A (N2a) cells except compound 7k (cytotoxic concentration, CC₅₀=30.8±0.3 μM), bearing the hydroxy group at the carbon-7 and -8 positions. However, this cytotoxic compound showed the least MAO (hMAO-A and hMAO-B) inhibitory activity. Interestingly, the non-cytotoxic compound 7f, bearing the diethylamino group at the C-7 position, showed the highest MAO inhibitory activity (hMAO-A: IC₅₀=1.27±0.66 μM and hMAO-B: IC₅₀=4.65±0.52 μM), MAO (A/B), non-selectivity (selectivity index, SI=3.66), reversible inhibition against hMAO-A enzyme, neuroprotection in H₂O₂-treated N2a cells, and capability of neutralizing free radicals in DPPH assay.

Conclusion: The 7-diethylamino-substituted 3-acylcoumarin-oxime derivative (compound 7f, bearing a diethylamino group at the C-7 position of the coumarin ring) can be considered a promising scaffold for developing new and more potent MAOI drugs for treating neurodegenerative disorders.