Combination of Detoxified Pneumolysin Derivative ΔA146Ply and Berbamine as a Treatment Approach for Breast Cancer

Abstract

Increasing evidence demonstrates that microorganisms and their products can modulate host responses to cancer therapies and contribute to tumor shrinkage via various mechanisms, including intracellular signaling pathways modulation and immunomodulation. Detoxified pneumolysin derivative ΔA146Ply is a pneumolysin mutant lacking hemolytic activity. To determine the antitumor activity of ΔA146Ply, the combination of ΔA146Ply and berbamine, a well-established antitumor agent, was used for breast cancer therapy, especially for triple-negative breast cancer. The efficacy of the combination therapy was evaluated in vitro using four breast cancer cell lines and in vivo using a synergistic mouse tumor model. We demonstrated that in vitro , the combination therapy significantly inhibited cancer cell proliferation, promoted cancer cell apoptosis, caused cancer cell-cycle arrest, and suppressed cancer cell migration and invasion. In vivo , the combination therapy significantly suppressed tumor growth and prolonged the median survival time of tumor-bearing mice partially through inhibiting tumor cell proliferation, promoting tumor cell apoptosis, and activating systemic antitumor immune responses. The safety analysis demonstrated that the combination therapy showed no obvious liver and kidney toxicity to tumor-bearing mice. Our study provides a new treatment option for breast cancer and lays the experimental basis for the development of ΔA146Ply as an antitumor agent.

Regulation of Cell-Signaling Pathways by Berbamine in Different Cancers

“…Detoxified pneumolysin derivative ΔA146Ply, a pneumolysin mutant, has been shown to be effective against cancer [ 52 ]. ΔA146Ply and berbamine synergistically reduced the growth of tumors in mice transplanted with 4T1 cells.…”

“…Furthermore, the ratio of Treg (regulatory T) cells was reported to be notably suppressed in mice combinatorically treated with ΔA146Ply and berbamine. Pulmonary metastatic lesions were also noted to be reduced in mice combinatorically treated with ΔA146Ply and berbamine [ 52 ].…”

Antidiabetic activity of Berberis brandisiana is possibly mediated through modulation of insulin signaling pathway, inflammatory cytokines and adipocytokines in high fat diet and streptozotocin-administered rats

“…Berbamine (Berb) is a bis-benzylisoquinoline alkaloid reported to be present in Berberis plants including Berberis aristata, Berberis vulgaris, Berberis poiretil schneid, Berberis amurensis and Berberis brandisiana ( Wang et al, 2009 ; Khan et al, 2016 ) belongs to Berberidaceae family. Berb has long been used in clinical settings for variety of ailments due to its reported anti-inflammatory effect by inhibiting (NF-κB, ERK1/2 and JNK signaling pathways) through the activation of macrophages and neutrophils ( Jia et al, 2017 ), anticancer ( Farooqi et al, 2022 ), antioxidant ( Sithuraj and Viswanadha, 2018 ), immunomodulatory ( Zhang et al, 2020 ), hepatoprotective ( Sharma et al, 2021 ), cardioprotective ( Sun et al, 1998 ; Zhang et al, 2012 ; Han et al, 2018 ; Sankaranarayanan et al, 2018 ) and antihypercholesterolemic effects.…”