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Proteasome Inhibitor-Loaded Micelles Enhance Antitumor Activity Through Macrophage Reprogramming by NF-κB Inhibition
Hailiang Wu1, Anqi Tao2, John D Martin2
1Innovation Center of NanoMedicine, Kawasaki Institute of Industrial Promotion, 3-25-14, Tonomachi, Kawasaki-ku, Kawasaki 210-0821, Japan.
Abstract:
Macrophage reprogramming toward a tumor-attacking phenotype is a promising treatment strategy, yet such strategies are scarce and it is not clear how to combine them with cytotoxic therapies that are often used to treat solid tumors. Here, we evaluate whether a micelle-encapsulated proteasome inhibitor, that is, the peptide aldehyde drug MG132, which is cytotoxic to cancer cells, can reprogram macrophages to attack the tumor. Through in vitro studies, we demonstrated that the proteasome inhibition reduces nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling-a known promoter of tumor-supporting macrophages and chemoresistance-in both cancer cells and macrophages. In in vivo studies, we showed that, although free MG132 did not affect the macrophage phenotype in tumors even at its maximum tolerated dose, the micellar formulation of MG132 safely achieved simultaneous cancer cell killing and macrophage reprogramming, thereby enhancing the antitumor efficacy in a syngeneic, orthotopic breast cancer model.
Insights
Micelle-encapsulated MG132 reprograms tumor-associated macrophages to attack cancer cells. This dual-action therapy enhances antitumor efficacy by combining cancer cell killing with macrophage reprogramming, overcoming limitations of cytotoxic therapies.
Area of Science:
- Immunology
- Oncology
- Nanomedicine
Background:
- Macrophage reprogramming is a promising cancer therapy, but combination strategies with cytotoxic treatments are lacking.
- Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling promotes tumor growth and chemoresistance.
- Developing effective combination therapies for solid tumors remains a challenge.
Purpose of the Study:
- To investigate if micelle-encapsulated MG132 can reprogram macrophages towards a tumor-attacking phenotype.
- To evaluate the potential of MG132 to overcome chemoresistance and enhance antitumor efficacy.
- To assess the safety and effectiveness of micellar MG132 in a breast cancer model.
Main Methods:
- In vitro studies assessing proteasome inhibition on NF-κB signaling in cancer cells and macrophages.
- In vivo studies using a syngeneic, orthotopic breast cancer model.
- Evaluation of micelle-encapsulated MG132 versus free MG132 on macrophage phenotype and tumor growth.
Main Results:
- Proteasome inhibition by MG132 reduced NF-κB signaling in both cancer cells and macrophages.
- Free MG132 did not alter macrophage phenotype in tumors, even at maximum tolerated dose.
- Micellar MG132 formulation achieved simultaneous cancer cell killing and macrophage reprogramming, enhancing antitumor efficacy.
Conclusions:
- Micelle-encapsulated MG132 is a viable strategy for simultaneous cancer cell killing and macrophage reprogramming.
- This approach offers a promising combination therapy for solid tumors, enhancing antitumor effects.
- Nanoparticle formulation of cytotoxic drugs can overcome limitations of free drugs in vivo.