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

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.

A nod to the bond between NOD2 and mycobacteria

“…Trained innate immunity elicited by BCG may be key to the utility of the bacillus [ 38 , 199 ]. Cancer is being targeted nonspecifically with BCG [ 200 ], Mip [ 201 , 202 ], and the Mtb extract Z-100 containing PGN [ 50 , 203 ]. With monocytes homozygous for the NOD2 frameshift mutation, trained innate immunity was defective after in vitro BCG [ 38 ] or gamma-irradiated BCG training [ 47 ].…”

Mycobacteria-Based Vaccines as Immunotherapy for Non-urological Cancers

“…MIP plus Survivin and alum immunization before tumor implantation seemed to induce a long protective effect [ 144 ]. More recently, MIP combined with 1’-S-1’-acetoxychavicol acetate and cisplatin reduced tumor volume of 4T1 tumors in mice with no observed toxicity, which is enough evidence to set up a clinical trial [ 145 ]. As observed in a melanoma mouse model ( Section 3.2 .…”