Combating multidrug resistance and metastasis of breast cancer by endoplasmic reticulum stress and cell-nucleus penetration enhanced immunochemotherapy

Abstract

Rationale: Multidrug resistance (MDR) and metastasis of breast cancer remain major hurdles in clinical anticancer therapy. The unsatisfactory outcome is largely due to insufficient cytotoxicity of chemotherapeutic agents and limited immunogenic cell death (ICD). On the other hand, efflux proteins, especially P-glycoprotein (P-gp), can recognize and promote the efflux of drugs from tumor cells. Methods: In this study, silver nanoparticles (Ag NPs) and peptide- functionalized doxorubicin ( P DOX) were used to prepare a theranostic nanocomposite (Ag-TF@ P DOX), which induced organelle-mediated immunochemotherapy and drug efflux protein inhibition in drug-resistant breast cancer cells (MCF-7/ADR) via a strategy based on endoplasmic reticulum (ER) stress and cell-nucleus penetration. Results: The silver nanoparticle-triggered persistent activation of ER stress synergizes with chemotherapy to enhance cytotoxicity and stimulate the ICD effect. It has the potential to enhance chemosensitivity by downregulating of P-gp expression due to the increased production of ATP-consuming chaperones. In addition, the novel peptide (CB5005), which not only penetrates the cell membrane but also has a nuclear localization sequence, is conjugated to DOX to improve both cellular internalization and intranuclear accumulation. Moreover, surface TA-Fe 3+ engineering endows the nanocomposite with ATP-responsive disassembly and ATP depletion properties to improve biocompatibility and decrease ATP-dependent drug efflux. Ag-TF@ P DOX has potential as a dual-mode (PAI/MRI) contrast-enhanced agent for realizing theranostic guidance. Conclusion: This theranostic nanocomposite greatly restricts the growth of drug-resistant breast tumors and activates a strong immune response as well, providing an opportunity for the development of therapeutics that reverse tumor MDR and metastasis at the subcellular level.

Development and validation of a novel endoplasmic reticulum stress-related lncRNA prognostic signature and candidate drugs in breast cancer

“…Clearly, the prognostic model has a good predictive value. It can be seen that the OS of patients in the high-risk group is lower than that in the low-risk group, reflecting that ERS as a cancer-promoting factor affects the prognosis of BC, which is consistent with the results of previous studies ( Jiang et al, 2022 ). A series of data also suggest that ER stress can promote tumor progression pass through multiple mechanisms including cancer cell survival and metastasis, therapy resistance, and angiogenesis ( Lee, 2007 ; Urra et al, 2016 ).…”

The Role of Silver Nanoparticles in the Diagnosis and Treatment of Cancer: Are There Any Perspectives for the Future?

“…Under stress-free conditions, PERK is bound by GRP78/BiP on the ER membrane, but ER stress facilitates the dissociation, phosphorylation, and oligomerization of PERK [ 108 ]. Activation of this signaling pathway resulted in an increase in cytoplasmic calcium levels and activation of caspase -12 [ 109 ]. Similar effects were also reported on the human breast cancer cells MDA-MB-231 and MCF-7 [ 110 , 111 ].…”

“…ER stress results in the activation of caspases as well as noncaspase proteases, for example, calpain [ 21 ]. ER stress and UPR may also be associated with changes in P-gp levels and functionality [ 109 , 112 ].…”

Modulating p-AMPK/mTOR Pathway of Mitochondrial Dysfunction Caused by MTERF1 Abnormal Expression in Colorectal Cancer Cells

“…AMPK activation can overcome multidrug resistance by decreasing the ATP-binding cassette (ABC) transporters (drug efflux pumps) that cause the efflux of hydrophobic compounds and xenobiotics such as chemotherapeutic drugs [ 32 , 33 ]. ABC transporter depends on the hydrolysis of ATP, and low ATP concentration has the strong ability to inhibit the ABC transporters [ 34 ]. The inhibition of mTOR also increases the drug sensitivity of cancer cells [ 35 ].…”