Anti-Cancer Effects of Synergistic Drug–Bacterium Combinations on Induced Breast Cancer in BALB/c Mice

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Abstract

Cancer development and progression are extremely complex due to the alteration of various genes and pathways. In most cases, multiple agents are required to control cancer progression. The purpose of this study is to investigate, using a mouse model, the synergistic interactions of anti-cancer agents, 1′-S-1′-acetoxychavicol acetate (ACA), Mycobacterium indicus pranii (MIP), and cisplatin (CDDP) in double and triple combinations to treat chemo-sensitize and immune-sensitize breast cancer. Changes in tumor volume and body weight were monitored. Organs were harvested and stained using hematoxylin–eosin for histopathological assessment. Milliplex enzyme-linked immunosorbent assay (ELISA) was performed to determine cytokine levels, while immunohistochemistry (IHC) was conducted on tumor biopsies to verify systemic drug effects. In vivo mouse models showed tumor regression with maintenance of regular body weight for all the different treatment regimens. IHC results provided conclusive evidence indicating that combination regimens were able to down-regulate nuclear factor kappa-B activation and reduce the expression of its regulated pro-inflammatory proteins. Reduction of pro-inflammatory cytokines (e.g., IL-6, TNF-α, and IFN-ɣ) levels were observed when using the triple combination, which indicated that the synergistic drug combination was able to significantly control cancer progression. In conclusion, ACA, MIP, and CDDP together serve as promising candidates for further development and for subsequent clinical trials against estrogen-sensitive breast cancer.

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The NCI60 human tumour cell line anticancer drug screen.

Robert Shoemaker (2006)

The US National Cancer Institute (NCI) 60 human tumour cell line anticancer drug screen (NCI60) was developed in the late 1980s as an in vitro drug-discovery tool intended to supplant the use of transplantable animal tumours in anticancer drug screening. This screening model was rapidly recognized as a rich source of information about the mechanisms of growth inhibition and tumour-cell kill. Recently, its role has changed to that of a service screen supporting the cancer research community. Here I review the development, use and productivity of the screen, highlighting several outcomes that have contributed to advances in cancer chemotherapy.

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Inhibiting NF-κB activation by small molecules as a therapeutic strategy.

Subash C Gupta, Chitra Sundaram, Simone Reuter … (2010)

Because nuclear factor-κB (NF-κB) is a ubiquitously expressed proinflammatory transcription factor that regulates the expression of over 500 genes involved in cellular transformation, survival, proliferation, invasion, angiogenesis, metastasis, and inflammation, the NF-κB signaling pathway has become a potential target for pharmacological intervention. A wide variety of agents can activate NF-κB through canonical and noncanonical pathways. Canonical pathway involves various steps including the phosphorylation, ubiquitination, and degradation of the inhibitor of NF-κB (IκBα), which leads to the nuclear translocation of the p50-p65 subunits of NF-κB followed by p65 phosphorylation, acetylation and methylation, DNA binding, and gene transcription. Thus, agents that can inhibit protein kinases, protein phosphatases, proteasomes, ubiquitination, acetylation, methylation, and DNA binding steps have been identified as NF-κB inhibitors. Because of the critical role of NF-κB in cancer and various chronic diseases, numerous inhibitors of NF-κB have been identified. In this review, however, we describe only small molecules that suppress NF-κB activation, and the mechanism by which they block this pathway. Copyright © 2010 Elsevier B.V. All rights reserved.

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Reduction of established spontaneous mammary carcinoma metastases following immunotherapy with major histocompatibility complex class II and B7.1 cell-based tumor vaccines.

Arlene S. Rosenberg, B A Pulaski (1998)

For many cancer patients, removal of primary tumor is curative; however, if metastatic lesions exist and are not responsive to treatment, survival is limited. Although immunotherapy is actively being tested in animal models against primary tumors and experimental metastases (i.v. induced), very few studies have examined immunotherapy of spontaneous, established metastatic disease. The shortage of such studies can be attributed to the paucity of adequate animal models and to the concern that multiple metastatic lesions may be more resistant to immunotherapy than a localized primary tumor. Here, we use the BALB/c-derived mouse mammary carcinoma, 4T1, and show that this tumor very closely models human breast cancer in its immunogenicity, metastatic properties, and growth characteristics. Therapy studies demonstrate that treatment of mice with established primary and metastatic disease with MHC class II and B7.1-transfected tumor cells reduces or eliminates established spontaneous metastases but has no impact on primary tumor growth. These studies indicate that cell-based vaccines targeting the activation of CD4+ and CD8+ T cells may be effective agents for the treatment of malignancies, such as breast cancer, where the primary tumor is curable by conventional methods, but metastatic lesions remain refractile to current treatment modalities.

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Journal

Journal ID (nlm-ta): Biomolecules

Journal ID (iso-abbrev): Biomolecules

Journal ID (publisher-id): biomolecules

Title: Biomolecules

Publisher: MDPI

ISSN (Electronic): 2218-273X

Publication date (Electronic): 18 October 2019

Publication date Collection: October 2019

Volume: 9

Issue: 10

Electronic Location Identifier: 626

Affiliations

[1 ]Institute of Biological Sciences (Genetics and Molecular Biology), Faculty of Science, University of Malaya, Kuala Lumpur 50603, Malaysia; menaga_04@ 123456yahoo.com (M.S.);

[2 ]Centre for Research in Biotechnology for Agriculture (CEBAR), University of Malaya, Kuala Lumpur 50603, Malaysia; hafizaarshad@ 123456um.edu.my

[3 ]Department of Pathology, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia; ksmun@ 123456ummc.edu.my

[4 ]Centre for Natural Product Research and Drug Discovery (CENAR) & Department of Chemistry, Faculty of Science, University of Malaya, Kuala Lumpur 50603, Malaysia; khalijah@ 123456um.edu.my

Author notes

[* ]Correspondence: hasima@ 123456um.edu.my ; Tel.: +603-79675921; Fax: +603-79675908

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Noor Hasima Nagoor https://orcid.org/0000-0003-3905-3129

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Publisher ID: biomolecules-09-00626

DOI: 10.3390/biom9100626

PMC ID: 6843452

PubMed ID: 31635311

SO-VID: c3be8075-36f5-455f-b398-7cce058c90f2

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Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Anti-Cancer Effects of Synergistic Drug–Bacterium Combinations on Induced Breast Cancer in BALB/c Mice

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Karger: Oncology

Most cited references 30

The NCI60 human tumour cell line anticancer drug screen.

Inhibiting NF-κB activation by small molecules as a therapeutic strategy.

Reduction of established spontaneous mammary carcinoma metastases following immunotherapy with major histocompatibility complex class II and B7.1 cell-based tumor vaccines.

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