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Huaier Enhances the Antitumor Activities of Black Phosphorus and Alleviates Nephrotoxicity by Regulating Mitophagy and Autophagy

ABSTRACT: Black phosphorus (BP) has shown promise as a nanomaterial for cancer therapy, but its nephrotoxicity limits its use. To improve BP anti-tumor effects and reduced toxic side effects, this study presents a novel approach to cancer therapy by combining BP with the traditional Chinese medicine Trametes robiniophila Murr (Huaier) to improve the treatment outcome for pancreatic cancer, a highly fatal malignancy. In 2D/3D cell lines, patient-derived organoids (PDOs) and mouse model, Huaier extraction is demonstrated to the antitumor effects of BP and mitigates BP-induced nephrotoxicity. RNA-sequencing analysis revealed that the combination of BP and Huaier enriched the mitophagy and ferroptosis pathways. While BP activates the mitophagy pathway to recycle damaged mitochondria, Huaier accelerates BP-induced mitochondrial dysfunction, leading to a mitochondrial burst and ultimately activating ferroptosis in PAAD cells. Furthermore, Huaier mitigates BP-induced nephrotoxicity and recovers cell viability by modulating the level of autophagy in proximal tubule epithelial cells. By synergizing BP with Huaier, we have achieved more potent antitumor activities with lower nephrotoxicity. These findings provide a promising strategy for treating PAAD in in vitro and in vivo models.

ORGANISM(S): Homo sapiens

PROVIDER: GSE229091 | GEO | 2023/08/01

REPOSITORIES: GEO

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Project description:Background We have recently constructed a DNA methylation classifier that can discriminate between pancreatic ductal adenocarcinoma (PAAD) liver metastasis and intrahepatic cholangiocarcinoma (iCCA) with high accuracy (PAAD-iCCA-Classifier). PAAD is one of the leading causes of cancer of unknown primary and diagnosis is based on exclusion of other malignancies. Therefore, our focus was to investigate whether the PAAD-iCCA-Classifier can be used to diagnose PAAD metastases from other sites. Methods For this scope, the anomaly detection filter of the initial classifier was expanded by 8 additional mimicker carcinomas, amounting to a total of 10 carcinomas in the negative class. We validated the updated version of the classifier on a validation set, which consisted of a biological cohort (n = 3579) and a technical one (n = 15). We then assessed the performance of the classifier on a test set, which included a positive control cohort of 16 PAAD metastases from various sites and a cohort of 124 negative control samples consisting of 96 breast cancer metastases from 18 anatomical sites and 28 carcinoma metastases to the brain. Results The updated PAAD-iCCA-Classifier achieved 98.21% accuracy on the biological validation samples, and on the technical validation ones it reached 100%. The classifier also correctly identified 15/16 (93.75%) metastases of the positive control as PAAD, and on the negative control, it correctly classified 122/124 samples (98.39%) for a 97.85% overall accuracy on the test set. We used this DNA methylation dataset to explore the organotropism of PAAD metastases and observed that PAAD liver metastases are distinct from PAAD peritoneal carcinomatosis and primary PAAD, and are characterized by specific copy number alterations and hypomethylation of enhancers involved in epithelial-mesenchymal-transition. Conclusions The updated PAAD-iCCA-Classifier (available at https://classifier.tgc-research.de/) can accurately classify PAAD samples from various metastatic sites and it can serve as a diagnostic aid.

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Huaier Enhances the Antitumor Activities of Black Phosphorus and Alleviates Nephrotoxicity by Regulating Mitophagy and Autophagy

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