Anti-Cancer Drugs最新文献

This study investigated 2-allyl-1,3-diphenyl-1,3-propanedione (DPAP), a dibenzoylmethane derivative, as a potentially more effective and safer alternative to dacarbazine for melanoma treatment. The antitumor activity of DPAP was assessed through comprehensive in-vitro, in-silico, and in-vivo experiments. In-vitro assays evaluated DPAP's IC 50 values against melanoma cells, benchmarking its efficacy against dacarbazine. Molecular analyses explored apoptosis mechanisms, emphasizing the roles of FAS receptors and caspase pathways. In-silico absorption, distribution, metabolism, excretion, and toxicity analysis provided insights into DPAP's pharmacokinetic profile, including absorption, distribution, metabolism, and toxicity. In-vivo studies examined its effects on tumor volume, vascular endothelial growth factor (VEGF) levels, and the histopathology of the liver, kidney, and lymph nodes. DPAP demonstrated significantly enhanced antitumor activity, reflected by markedly lower IC 50 values compared with dacarbazine, underscoring its superior efficacy and specificity toward tumor cells. Molecular assays confirmed that DPAP induces apoptosis through modulation of FAS receptors and activation of caspase pathways. In-silico results revealed favorable pharmacokinetic properties, including high intestinal absorption and good tissue distribution, with no evidence of carcinogenic potential. Notably, in-vivo experiments showed that DPAP effectively reduced tumor volume and VEGF levels, while also preventing hepatotoxicity and nephrotoxicity. In addition, it inhibited the migration of tumor cells to lymph nodes. These findings position DPAP as a promising candidate for melanoma treatment, particularly as a topical therapeutic, offering enhanced efficacy and safety compared with existing treatments. DPAP is a promising candidate for melanoma treatment, particularly through topical application, offering a safer and more effective alternative to current treatments.

Almonertinib, a representative epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), is the first-line standard treatment for EGFR-mutant advanced non-small-cell lung cancer; however, it may induce drug-related interstitial lung disease (ILD). This case report presents a 67-year-old female with advanced lung adenocarcinoma, who was diagnosed with an EGFR exon 19 deletion mutation. After 2 months of first-line almonertinib treatment (110 mg/day), a PR was achieved; however, progressive respiratory distress emerged. Chest computed tomography revealed ground-glass opacities accompanied by grid-like changes in both lungs, leading to a diagnosis of EGFR-TKI-related ILD (grade 2). Following glucocorticoid treatment and medication discontinuation, the lung lesions improved. Given the persistent tumor activity, the patient was switched to firmonertinib (80 mg/day) for targeted therapy. This switch did not lead to a recurrence of ILD symptoms, with a progression-free survival exceeding 5 months and good tolerability. This suggests that for patients with ILD associated with almonertinib and firmonertinib may serve as an effective and safe alternative. Closely monitoring ILD in clinical practice and promptly switching to similar drugs may avoid chemotherapy intervention and optimize treatment strategies. This case marks the first report of clinical experience achieving sustained remission by switching to a similar drug, firmonertinib, in patients with ILD related to almonertinib.

Among solid tumors, malignant melanoma (MM) has the highest risk of metastasis to the leptomeninges, for which a specific therapeutic regimen has not been established yet. This case report describes a rapid partial response to leptomeningeal disease (LMD) in a patient with a BRAF V600K-mutated MM. A 69-year-old man affected by metastatic melanoma was initially treated with benefit with targeted therapy with encorafenib and binimetinib, which was discontinued several times because of toxicity or intolerance, and then with dabrafenib and trametinib, which were also poorly tolerated. During the treatment pause, the patient, who had refused to receive immunotherapy developed LMD and was started again on targeted therapy with reduced dosage of encorafenib and binimetinib. A few days after starting this treatment, MRI showed an important reduction of the perilesional edema and then, after a few months, a disease response. The patient had a long survival of approximately 14 months from this diagnosis. To the best of our knowledge, this is the first report describing rapid radiological response, clinical benefit, and prolonged survival with encorafenib and binimetinib in patients affected by LMD from melanoma.

Salivary duct carcinoma (SDC), an aggressive and relatively rare tumor, accounts for approximately 10% of all salivary gland malignancies. We report a case of a patient with a metastatic, human epidermal growth factor receptor 2 (HER2)-positive parotid SDC efficiently treated with docetaxel and trastuzumab combination after multiple series of chemotherapies. A 61-year-old man presented with SDC. After adjuvant radiotherapy, imaging revealed multiple metastatic lesions in the lungs. Systemic treatment with carboplatin and paclitaxel was initiated. After disease progression, doxorubicin, vinorelbine, and capecitabine were performed. Neurotrophic tropomyosin receptor kinase and AR (androgen receptor) were negative. Immunohistochemistry determined a HER2-positive score of 3. After multiple chemotherapy, the patient was started with combination of docetaxel and trastuzumab. A complete response was obtained after 3 months of treatment in the patient. In conclusion, SDCs are highly aggressive malignant tumors. Targeted therapy with trastuzumab targeting HER2 overexpression is a reasonable option in metastatic settings.

This study aimed to investigate the role of forkhead box O1 (FOXO1) in carboplatin-resistant retinoblastoma (RB) cells, focusing on its subcellular distribution and regulation through ubiquitin-dependent degradation mediated by denticleless homolog (DTL). The study sought to elucidate the molecular mechanisms underlying carboplatin resistance in RB and explore potential therapeutic strategies to overcome chemoresistance. Carboplatin-resistant RB cell lines (Y79/CBP and WERI-Rb-1/CBP) were established by incremental drug exposure. Bioinformatics analysis of the GSE111168 dataset identified differentially expressed genes associated with ubiquitination pathways. DTL expression was modulated using adeno-associated virus-mediated knockdown and overexpression. FOXO1 protein levels, subcellular localization, and ubiquitination were assessed via western blotting, immunofluorescence, and coimmunoprecipitation (Co-IP). The effects of DTL knockdown and LOM612 treatment on cell proliferation, apoptosis, and tumor growth were evaluated in vitro and in vivo using xenograft models. FOXO1 expression and nuclear localization were significantly reduced in carboplatin-resistant RB cells, with elevated levels of FOXO1 ubiquitination. Proteasome inhibitors preserved FOXO1 protein levels, implicating the ubiquitin-proteasome system in its degradation. DTL was identified as a significantly overexpressed gene in both resistant cells and patient-derived samples. Silencing DTL increased FOXO1 protein expression and nuclear accumulation, while Co-IP confirmed the interaction between DTL and FOXO1, mediated by the WD40 domain of DTL. Combined DTL knockdown and LOM612 treatment synergistically inhibited cell proliferation and invasion, promoted apoptosis in vitro, and significantly reduced tumor growth and induced apoptosis in vivo. DTL-mediated ubiquitination and degradation of FOXO1 play a critical role in carboplatin resistance in RB. Dual targeting of DTL and FOXO1 nuclear translocation may represent a promising therapeutic strategy to overcome chemoresistance and improve clinical outcomes in RB.

Pancreatic cancer is characterized by aggressiveness and poor prognosis. The development of gemcitabine resistance, especially tumor-associated macrophage (TAM) -induced resistance in the tumor microenvironment, has greatly limited its therapeutic effectiveness. This study investigates the effects and underlying mechanisms of the plant-derived bioactive compound α-asarone in reversing gemcitabine resistance induced by TAMs in pancreatic cancer, offering potential therapeutic alternatives. Flow cytometry was used to assess the cell cycle and apoptosis in pancreatic cancer cells. Transforming growth factor-beta 1 (TGF-β1) secretion was measured by ELISA, and Cell Counting Kit-8 assays to evaluate the survival of PANC-1 cells treated with gemcitabine. Western blotting and quantitative real-time PCR were used to analyze growth factor independent 1 (Gfi-1) expression and its association with gemcitabine resistance. α-Asarone effectively reversed gemcitabine resistance in pancreatic cancer cells. Treatment with α-asarone reduced TGF-β1 levels in TAM condition medium, which in turn led to the upregulation of Gfi-1 expression. Gfi-1 was found to negatively regulate the expression of drug resistance factors, including connective tissue growth factor (CTGF) and high mobility group box 1 (HMGB1), thereby reversing gemcitabine resistance in pancreatic cancer cells. Those results indicate that α-asarone enhances Gfi-1 expression, downregulates CTGF and HMGB1, and restores gemcitabine sensitivity by reducing TGF-β1 secretion from TAMs. α-Asarone can effectively reverse gemcitabine resistance in pancreatic cancer by reducing TGF-β1 secretion from TAMs, upregulating Gfi-1, and downregulating resistance factors such as CTGF and HMGB1. This restoration of gemcitabine sensitivity may improve the therapeutic efficacy of gemcitabine in pancreatic cancer treatment.

Nuclear protein in testis (NUT) carcinoma is a rare disease characterized by aggressive and rapid progression. There is no standard management of primary pulmonary NUT carcinoma until now, and the median overall survival is only 4.4 months. Here, we describe a case where a 48-year-old woman presented with a dry, lasting half a month, and she was diagnosed with primary pulmonary NUT carcinoma and was given chemotherapy, immunotherapy, antiangiogenesis therapy, and palliative radiotherapy. When secondary tumor progression, she was conducted an organoid drug sensitivity test for better guide therapy. The initial two cycles of first-line and second-line treatments in our patient proved effective and improved the overall survival to more than 8 months. This is the first report of the use of an organoid drug sensitivity test for primary pulmonary NUT carcinoma. It provides a new approach for selecting drugs, particularly when multiple lines of treatment have proven ineffective and the next steps are unclear.

ABL1 and ABL2 are putative drivers of medulloblastoma leptomeningeal dissemination. ABL1/ABL2 inhibitors, nilotinib and asciminib, are P-glycoprotein substrates. The purpose of this work is to elucidate P-glycoprotein expression in the brain/brain tumors and to determine if P-glycoprotein inhibition increases plasma and brain concentrations and medulloblastoma cytotoxicity of nilotinib and asciminib. ABCB1 (P-glycoprotein) mRNA expression was analyzed from multiple datasets of brain and brain tumor specimens. Cytotoxicity assays of medulloblastoma cells were conducted. In a mouse model, the pharmacokinetics of asciminib and nilotinib, with and without tariquidar, were determined using LC/MS. ABCB1 mRNA expression varied by brain region and was significantly lower in the cerebellum ( P  < 0.05). There was a bimodal increase in brain ABCB1 expression at ages 0-3 and 21-23 ( P  < 0.05). ABCB1 expression in pediatric brain tumors was similar to normal brain. The addition of tariquidar significantly reduced medulloblastoma cell viability compared to asciminib alone ( P  < 0.01). Tariquidar increased asciminib plasma and brain concentrations at 24 h ( P  = 0.0005 and P  = 0.0002, respectively) and nilotinib brain concentrations at 3 h ( P  = 0.0009). Tariquidar increased the area under the curve (AUC) brain : plasma ratio of asciminib from 0.33 to 10.16% and of nilotinib from 1.16 to 9.61%. Tariquidar prolonged the plasma half-life of asciminib from 2.21 to 10.49 h and nilotinib from 7.63 to 14.64 h. P-glycoprotein inhibition increased the brain concentrations, AUC, and half-life of asciminib and nilotinib and increased cytotoxicity in medulloblastoma cells.

Immunotherapy shows limited efficacy in microsatellite-stable (MSS) colorectal cancer. This case report describes a 40-year-old male with left-sided kirsten rat sarcoma viral oncogene homolog (KRAS)/v-raf murine sarcoma viral oncogene homolog B (BRAF) wild-type, MSS colorectal cancer and liver metastases who achieved complete regression of metastases following first-line treatment with toripalimab, cetuximab, and FOLFIRI (irinotecan + fluorouracil + leucovorin), enabling curative-intent surgical resection. The patient achieved a progression-free survival of 16 months and an overall survival exceeding 20 months. The regimen demonstrated excellent tolerability without severe adverse events, suggesting that this triple combination represents a promising strategy for conversion therapy in advanced MSS colorectal cancer.

9-Hexadecenoic acid (9-HA) possesses anti-tumor properties. However, the effects of 9-HA on gastric cancer are scarcely reported. The present study aimed to investigate the effects of 9-HA on gastric cancer. mRNA levels were detected by reverse transcription quantitative PCR. Protein expression was detected by western blot. Cell behaviors were analyzed using Cell Counting Kit-8, colony formation, transwell, and propidium iodide staining assays. Co-localization of PTPN1 and FTH1 was determined using fluorescence in situ hybridization assay. In vivo assay was conducted to further verify the effects of 9-HA on gastric cancer. 9-HA suppressed the malignant behavior of gastric cancer. Moreover, 9-HA promoted iron-overload-dependent ferroptosis of gastric cancer in vivo and in vitro. Traditional Chinese medicine systems pharmacology predicted that 9-HA could target PTPN1, which was upregulated in gastric cancer cells. PTPN1-mediated phosphorylation of FTH1 contributed to the latter degradation. Overexpressed PTPN1 alleviated the effects of 9-HA, promoting the aggressiveness of gastric cancer and suppressing tumor cell ferroptosis. Interestingly, overexpressed PTPN1 antagonized the effects of 9-HA, promoted tumor growth, and inhibited the ferroptosis of gastric cancer. In summary, 9-HA-mediated downregulation of PTPN1 drives ferroptosis and inhibit the aggressiveness of gastric cancer. Thence, 9-HA may be an alternative strategy for gastric cancer.