Improved chemosensitivity following mucolytic therapy in patient-derived models of mucinous appendix cancer

Dilly, Ashok K.; Honick, Brendon D.; Frederick, Robin; Elapavaluru, Anuleka; Velankar, Sachin; Makala, Himesh; Hitchens, T. Kevin; Foley, Lesley M.; Guo, Jianxia; Beumer, Jan H.; Rigatti, Lora H.; Bartlett, David L.; Choudry, Haroon A.

doi:10.1016/j.trsl.2020.10.005

Cited by 12 publications

(9 citation statements)

References 38 publications

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“…The selection of an effective preclinical model for MAA is necessary. However, a limited number of preclinical studies on MAA tumors have been done ( 22 , 23 ). Due to convenience and reliable growth, tumor cell lines have been widely used in preclinical research; however, 2D culture models do not mimic tumor microenvironments and homogenization significantly affects chemotherapeutic outcomes ( 12 ).…”

Section: Discussionmentioning

confidence: 99%

Organoids From Mucinous Appendiceal Adenocarcinomas as High-Fidelity Models for Individual Therapy

et al. 2022

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BackgroundMucinous appendiceal adenocarcinoma (MAA) is a rare, heterogeneous disease. Patients with unrespectable mucinous appendiceal adenocarcinoma presenting with peritoneal spread are treated by intraperitoneal chemotherapy, hyperthermic intraperitoneal chemotherapy, systemic chemotherapy, or targeted therapy. However, there are no guidelines for efficacious drugs against mucinous appendiceal adenocarcinoma. Therefore, relevant high-fidelity models should be investigated to identify effective drugs for individual therapy.MethodsSurgical tumor specimens were obtained from a mucinous appendiceal adenocarcinoma patient. The tissue was digested and organoid culture was established. H&E and immunohistochemistry staining as well as DNA sequencing was performed on tissue and organoid. The pathological characteristics and gene mutations of the organoid were compared to those of the original tumor. Drug sensitivity tests were performed on organoid and the patient clinical responds to chemotherapy and targeted therapy was compared.ResultsOrganoids were successfully established and stably passaged. Pathological characteristics of organoids including H&E staining and expression of protein markers (CK20, CDX-2, STAB2, CD7, PAX8) were consistent to those of the original tumor. Moreover, the organoids carried the same gene mutations as the primary tumor. Sensitivity of the organoids to chemotherapeutic drugs and tyrosine kinase inhibitors included: 5-FU (IC50 43.95 μM), Oxaliplatin (IC50 23.49 μM), SN38 (IC50 1.02 μM), Apatinib (IC50 0.10 μM), Dasatinib (IC50 2.27 μM), Docetaxel (IC50 5.26 μM), Regorafenib (IC50 18.90 μM), and Everolimus (IC50 9.20 μM). The sensitivities of organoid to these drugs were comparable to those of the patient's clinical responses.ConclusionThe mucinous appendiceal adenocarcinoma organoid model which retained the characteristics of the primary tumor was successfully established. Combined organoid-based drug screening and high throughput sequencing provided a promising way for mucinous appendiceal adenocarcinoma treatment.

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Section: Discussionmentioning

confidence: 99%

Organoids From Mucinous Appendiceal Adenocarcinomas as High-Fidelity Models for Individual Therapy

et al. 2022

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“…Researchers developed a combination of bromelain and N-acetylcysteine to achieve mucolysis and significantly enhanced the chemotherapeutic effect in MCP PDX. 166 Moreover, boosting the bioavailability of drugs by chemical modification is essential to improve the efficacy of chemotherapy. Modified gemcitabine, termed 4-N-stearoylGem, strongly inhibited tumor growth in pancreatic cancer PDX and surprisingly showed an antiangiogenic effect by reducing vascular endothelial growth factor receptors expression.…”

Section: Pdx Model In Chemotherapy Researchmentioning

confidence: 99%

Patient-derived xenograft models in cancer therapy: technologies and applications

Liu

Cai

et al. 2023

Sig Transduct Target Ther

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Patient-derived xenograft (PDX) models, in which tumor tissues from patients are implanted into immunocompromised or humanized mice, have shown superiority in recapitulating the characteristics of cancer, such as the spatial structure of cancer and the intratumor heterogeneity of cancer. Moreover, PDX models retain the genomic features of patients across different stages, subtypes, and diversified treatment backgrounds. Optimized PDX engraftment procedures and modern technologies such as multi-omics and deep learning have enabled a more comprehensive depiction of the PDX molecular landscape and boosted the utilization of PDX models. These irreplaceable advantages make PDX models an ideal choice in cancer treatment studies, such as preclinical trials of novel drugs, validating novel drug combinations, screening drug-sensitive patients, and exploring drug resistance mechanisms. In this review, we gave an overview of the history of PDX models and the process of PDX model establishment. Subsequently, the review presents the strengths and weaknesses of PDX models and highlights the integration of novel technologies in PDX model research. Finally, we delineated the broad application of PDX models in chemotherapy, targeted therapy, immunotherapy, and other novel therapies.

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“…Bromelain is made up of a mixture of hydrolytic enzymes, not only with endopeptidase activity, hydrolyzes esters, amides and glycosidic bonds, while NAC can reduce disulfide bridges. Such a combination impaired the complex lattice framework of mucus thus improving drug delivery and increasing cytotoxic effects ( 150 ).…”

Section: Synergistic Anticancer Effects Of Bromelain Combined With Ch...mentioning

confidence: 99%

Anticancer properties of bromelain: State-of-the-art and recent trends

Pezzani

Jiménez-Garcia²,

Capó³

et al. 2023

Front. Oncol.

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Bromelain is a key enzyme found in pineapple (Ananas comosus (L.) Merr.); a proteolytic substance with multiple beneficial effects for human health such as anti-inflammatory, immunomodulatory, antioxidant and anticarcinogenic, traditionally used in many countries for its potential therapeutic value. The aim of this updated and comprehensive review focuses on the potential anticancer benefits of bromelain, analyzing the cytotoxic, apoptotic, necrotic, autophagic, immunomodulating, and anti-inflammatory effects in cancer cells and animal models. Detailed information about Bromelain and its anticancer effects at the cellular, molecular and signaling levels were collected from online databases such as PubMed/MedLine, TRIP database, GeenMedical, Scopus, Web of Science and Google Scholar. The results of the analyzed studies showed that Bromelain possesses corroborated pharmacological activities, such as anticancer, anti-edema, anti-inflammatory, anti-microbial, anti-coagulant, anti-osteoarthritis, anti-trauma pain, anti-diarrhea, wound repair. Nonetheless, bromelain clinical studies are scarce and still more research is needed to validate the scientific value of this enzyme in human cancer diseases.

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Improved chemosensitivity following mucolytic therapy in patient-derived models of mucinous appendix cancer

Cited by 12 publications

References 38 publications

Organoids From Mucinous Appendiceal Adenocarcinomas as High-Fidelity Models for Individual Therapy

Organoids From Mucinous Appendiceal Adenocarcinomas as High-Fidelity Models for Individual Therapy

Patient-derived xenograft models in cancer therapy: technologies and applications

Anticancer properties of bromelain: State-of-the-art and recent trends

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