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Conquering triple-negative breast cancer

2020-09-24
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According to the 2018 International Agency for Research on Cancer (IARC) survey data, the incidence of breast cancer in female cancers worldwide is 24.2%, ranking first among female cancers, of which 52.9% occur in developing countries. From the onset, the incidence of breast cancer gradually rises after age 20, reaching a peak between the ages of 45 and 50.

Triple-negative breast cancer (TNBC) is one of all breast cancers. It is called "three negatives" because the three main therapeutic targets of estrogen receptor, progesterone receptor, and HER-2 are negative. About 15% of all breast cancers. This type of breast cancer is considered the "most toxic and dangerous" breast cancer due to the lack of targets and the high risk of recurrence and metastasis. Among them, triple-negative breast cancer, progressing after many rounds of treatment, is even closer to "exhaustion." The proportion of patients with tumor shrinkage after conventional treatment is less than 10%.

Nature is full of harmful compounds, but medical scientists have shown us how to use them to benefit humanity and even become life-saving drugs. Recently, a breakthrough discovery by Australian scientists is the latest example. The team demonstrated how an ingredient in bee venom could be used as a "potent" weapon against breast cancer. This research was conducted at the Harry Perkins Institute of Medical Research in Australia. We have seen how specific peptides and proteins in bee venom transport drugs across the blood-brain barrier, but Dr. Duffy's research focuses on how It is used to treat various breast cancers. Her research focuses on an active compound called melittin in bee venom and how it induces cell death in different clinical subtypes of breast cancer. The study was published in the journal Nature Precision Oncology.

Medicilon boasts nearly 300 tumor evaluation models. At the same time, we are empowering innovative therapies to comprehensively evaluate and study immuno-oncology. We have completed model establishment and efficacy evaluation of immuno-therapies such as CAR-T, TCR-T, CAR-NK, oncolytic virus, antibody (monoclonal antibody, double antibody, polyclonal antibody, etc.), siRNA, AAV.

Nature Precision Oncology
Source: npj Precision Oncology

Bee venom and melittin can specifically reduce the viability of breast cancer cells

breast cancer cells

Source: npj Precision Oncology

To evaluate the anticancer efficacy and selectivity, the researchers assessed bee venom collected from Australia. The poison showed high anticancer selectivity, with higher efficacy in TNBC and HER2-rich breast cancer cell lines. They are intraluminal breast cancer cells and have the most negligible impact on normal cells.

The researchers developed a mouse monoclonal antibody that recognizes melittin to evaluate the relative abundance of melittin in all honeybee and bumblebee venom samples by ELISA. According to the above activity study, the close lot of melittin is not significantly different in all bee venom samples at various locations (two-way analysis of variance, p>0.999). However, the concentration of melittin in the honeybee samples was significantly higher compared to the bumblebee venom and isotype IgG controls.

The anticancer effect of melittin was confirmed by in vitro blocking experiments, in which the researchers used anti-melittin antibodies to rescue the cell viability of HDFa and SUM159 cells. These data indicate that the melittin present in bee venom is the most prominent bioactive anticancer compound in the venom studied.

Bee venom and melittin can induce breast cancer cell death.

To find out the mechanism of cell death, TNBC cells were treated with bee venom or melittin IC50 for 18 and 24 hours, respectively, and treated with lysed caspase-3 to quantify the death of apoptotic cells. Western blotting confirmed the induction of caspase-3 lysed in SUM159 cells. Melittin alone can induce higher levels of cancer cell apoptosis than bee venom at 18 and 24 hours after treatment.

Bee venom and melittin can induce breast cancer cell death

induce death of breast cancer cells

Source: npj Precision Oncology

To quantify the apoptotic, necrotic, or dead cell population after treatment, the researchers performed the annexin V-FITC cell apoptosis detection analysis. SUM159 cells were exposed to vehicle, bee venom, or melittin using IC50 concentration and processed by flow cytometry after 60 minutes of treatment. The researchers found that compared with bee venom (8.3±1.9%) and vehicle control (4.8±0.4%), samples treated with melittin (23.6±5.7%) had significantly later apoptotic or necrotic cells (23.6±5.7) %). Still, there was no significant difference in the levels of early apoptosis or necrotic cells. To characterize the kinetics of cell death in a short period, the cell viability of HDFa, SKBR3, and SUM159 cells treated with melittin at IC50 concentration for up to 1 hour was measured. Bee venom will rapidly reduce cell viability, and there is no significant difference between normal cells and cancer cell lines within one hour.

On the contrary, from 10 minutes, melittin significantly reduced the viability of the two breast cancer cells compared with normal cells. From 30 minutes, SUM159 was considerably higher than SKBR3 (two-way ANOVA, p<0.0001). Confocal microscopy and scanning electron microscopy of live cells in SKBR3 and SUM159 cells indicate that the plasma membrane will quickly rupture and shrink within 10 to 60 minutes when treated with melittin and melittin.

Bee venom and melittin inhibit RTK phosphorylation

inhibit RTK phosphorylation

Source: npj Precision Oncology

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In SUM159, bee venom and melittin significantly down-regulate p-EGFR within 10 to 20 minutes. SUM159 cells trigger ERK signals due to negative regulatory feedback loops in MAPK and Akt pathways to protect cells from the release of apoptotic cell death. The anti-melittin antibody showed that the melittin content in the lysate of both cell lines increased over time, and the signal of melittin treatment signal in the two cell lines was more robust than bee venom. To characterize the effect on signaling pathways in another TNBC model, the researchers performed western blot analysis on MDA-MB-231 cells, in which EGF treatment phosphorylates EGFR and induces EGFR expression. Unlike SUM159 cells, the stimulation of EGFR by EGF is not related to the increase of p-Akt phosphorylation, which may be due to the separation between EGFR signaling and the Akt pathway.

Considering that breast cancer cells rich in TNBC and HER2 are highly dependent on the activation of EGFR and HER2, the researchers conducted a bioluminescence resonance energy transfer (BRET) experiment to determine whether melittin interferes with the binding of EGF and EGFR. The BRET signal of TAMRA-EGF and FITC-DEDE-melittin increased dose-dependent, while the amplitude of FITC-melittin was smaller. At the same concentration, the BRET ratio of FITC-DEDE-melittin is much higher than that of FITC-melittin, and the maximum BRET ratio can be reached quickly at each dose. To determine the specificity of melittin binding to EGFR at the EGF binding site, saturated BRET analysis was performed to evaluate the competition of EGF with each NanoLuc-EGFR-binding peptide. When one µM EGF is present, the binding of TAMRA-EGF to NanoLuc-EGFR is saturated and significantly reduced. At the same time, the BRET signals of FITC melittin and FITC-DEDE-melittin are not soggy. In the presence or absence of 1 µM EGF, There is no significant difference in the following, which indicates that neither melittin nor DEDE-melittin binds to the EGF binding site.

In short, melittin is integrated into the plasma membrane of cancer cells through the charged sequence at the C-terminus, thereby inducing plasma membrane remodeling and destruction. The BRET data showed that melittin could be located within 10 nm from the RTK without interfering with the binding sites of endogenous growth factors.

Results and discussion

Studies have shown that bee venom and melittin can inhibit ligand-induced phosphorylation of EGFR and HER2, thereby dynamically regulating downstream signaling pathways in breast cancer cells. Melittin can also enter cells to directly or indirectly restrict downstream signal transduction pathways. The selectivity of melittin for HER2-driven tumors also provides a further case for its combined use with HER2-targeted drugs. The membrane destruction properties of melittin can enhance the intrinsic dynamics of its cytotoxic payload.

The researchers also revealed new opportunities to modify specific regions of melittin to further improve the efficacy and targeting specificity of malignant cells. Engineered targeting peptides, such as RGD1-melittin, can be delivered intravenously to achieve more selective homing and uptake into tumor cells. However, further studies on these peptides' toxicity and maximum tolerated dose will be required before human trials.

Melittin can be used globally and provides cost-effective and easy-to-use treatment options in some remote or underdeveloped areas. At present, further research is needed to evaluate whether the venom of certain genotypes of bees has more muscular or specific anticancer activity and can be used. Overall, this study's results can assist in developing new treatments for multiple cancers associated with frequent drug resistance and poor prognosis. Medicilon, as a new drug research and development CRO, will continue to pay attention to this research progress, hoping to help breast cancer new drug research and development.

About Medicilon

Medicilon (stock code: 688202) was established in 2004 and is headquartered in Shanghai. It is committed to providing a full range of preclinical new drug research services for global pharmaceutical companies, research institutions, and scientific researchers. Medicilon's one-stop integrated service helps customers accelerate the development of new drugs with solid project management and more efficient and cost-effective R&D services. The services cover medical preclinical new drug research, including drug discovery, pharmaceutical research, and clinical trials. Pre-research. Medicilon grows with high-quality customers at home and abroad and provides new drug research and development services to more than 700 customers worldwide. Medicilon will continue to base itself on a global perspective, gather Chinese innovation, and contribute to human health!


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