Skip to main content
Top

Open Access 04-05-2024 | Acetylcysteine | Peritoneal Surface Malignancy

Enhancing the Efficacy of HIPEC Through Bromelain: A Preclinical Investigation in Appendiceal Cancer

Authors: Nadeem Wajih, PhD, Richard A. Erali, MD, MPH, Steven D. Forsythe, PhD, Cecilia R. Schaaf, DVM, PhD, Perry Shen, MD, Edward A. Levine, MD, Shay Soker, PhD, David L. Morris, MD, PhD, Konstantinos I. Votanopoulos, MD, PhD

Published in: Annals of Surgical Oncology

Login to get access

Abstract

Introduction

Appendiceal cancer (AC) excessive mucin production is a barrier to heated intraperitoneal chemotherapy (HIPEC) drug delivery. Bromelain is a pineapple stem extract with mucolytic properties. We explored bromelain treatment effects against mucinous AC in a patient-derived tumor organoid (PTO) model and an AC cell line.

Patients and Methods

PTOs were fabricated from tumor specimens obtained from patients with AC undergoing cytoreductive surgery with HIPEC. PTOs underwent HIPEC treatment with bromelain, cisplatin, and mitomycin C (MMC) at 37 °C and 42 °C with and without bromelain pretreatment.

Results

From October 2020 to May 2023, 16 specimens were collected from 13 patients with low-grade (12/16, 75%) and high-grade AC (4/16, 25%). The mucin-depleting effects of bromelain were most significant in combination with N-acetylcysteine (NAC) compared with bromelain (47% versus 10%, p = 0.0009) or NAC alone (47% versus 12.8%, p = 0.0027). Bromelain demonstrated > 31% organoid viability reduction at 60 min (p < 0.001) and > 66% in 48 h (p < 0.0001). Pretreatment with bromelain increased cytotoxicity of both cisplatin and MMC HIPEC conditions by 31.6% (p = 0.0001) and 35.5% (p = 0.0001), respectively. Ki67, CK20, and MUC2 expression decreased after bromelain treatment; while increased caspase 3/7 activity and decreased Bcl-2 (p = 0.009) and Bcl-xL (p = 0.01) suggest induction of apoptosis pathways. Furthermore, autophagy proteins LC3A/B I (p < 0.03) and II (p < 0.031) were increased; while ATG7 (p < 0.01), ATG 12 (p < 0.04), and Becline 1(p < 0.03), expression decreased in bromelain-treated PTOs.

Conclusions

Bromelain demonstrates cytotoxicity and mucolytic activity against appendiceal cancer organoids. As a pretreatment agent, it potentiates the cytotoxicity of multiple HIPEC regimens, potentially mediated through programmed cell death and autophagy.
Appendix
Available only for authorised users
Literature
8.
13.
go back to reference Amini A, Masoumi-Moghaddam S, Morris DL. Utility of bromelain and N-acetylcysteine in treatment of peritoneal dissemination of gastrointestinal mucin-producing malignancies. Anticancer Res. 2016;36:3224–5. Amini A, Masoumi-Moghaddam S, Morris DL. Utility of bromelain and N-acetylcysteine in treatment of peritoneal dissemination of gastrointestinal mucin-producing malignancies. Anticancer Res. 2016;36:3224–5.
21.
go back to reference Ltd, M. P. A Phase 2, Multi-centre study of BromAc for recurrent peritoneal mucinous tumour or pseudomyxoma peritonei. Report No. NCT03976973, (clinicaltrials.gov, 2022). Ltd, M. P. A Phase 2, Multi-centre study of BromAc for recurrent peritoneal mucinous tumour or pseudomyxoma peritonei. Report No. NCT03976973, (clinicaltrials.gov, 2022).
Metadata
Title
Enhancing the Efficacy of HIPEC Through Bromelain: A Preclinical Investigation in Appendiceal Cancer
Authors
Nadeem Wajih, PhD
Richard A. Erali, MD, MPH
Steven D. Forsythe, PhD
Cecilia R. Schaaf, DVM, PhD
Perry Shen, MD
Edward A. Levine, MD
Shay Soker, PhD
David L. Morris, MD, PhD
Konstantinos I. Votanopoulos, MD, PhD
Publication date
04-05-2024
Publisher
Springer International Publishing
Keyword
Acetylcysteine
Published in
Annals of Surgical Oncology
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-024-15355-0
Webinar | 06-02-2024 | 20:00 (CET)

Mastering chronic pancreatitis pain: A multidisciplinary approach and practical solutions

Severe pain is the most common symptom of chronic pancreatitis. In this webinar, experts share the latest insights in pain management for chronic pancreatitis patients. Experts from a range of disciplines discuss pertinent cases and provide practical suggestions for use within clinical practice.

Sponsored by: Viatris

Developed by: Springer Healthcare