Table 3 Shows various Agents that target cell surface GRP78
Agents that target cell surface GRP78 | Types | References |
|---|---|---|
Phytochemicals | Fungi: Fungi, such as mushrooms, contain p-Coumaric acid and caffeic acid, both of which have been shown to have a binding affinity for the GRP78 SBD beta region in computational models. These compounds have been proposed as potential inhibitors for GRP78 to counteract its overexpression in cancer cells Epigallocatechin3gallate: Another compound of interest is epigallocatechin-3-gallate (EGCG), a polyphenol found in green tea. EGCG has demonstrated an anti-proliferative effect on melanoma and breast cancer cells. Moreover, EGCG has been found to directly interact with the ATP-binding site of GRP78, effectively inhibiting GRP78 function by competing with ATP binding. This interaction has the potential to disrupt the proper folding and processing of proteins, leading to cellular stress and potential cancer cell death | |
Peptides | Several peptides and peptide conjugates have been investigated for their ability to interact with GRP78 and exert anti-cancer effects GMP1 peptide: The GMBP1 peptide has been utilized to reverse multidrug resistance (MDR) in stomach cancer. It functions by utilizing GRP78 as a receptor, facilitating its internalization into cancer cells through the transferrin-related pathway. By targeting GRP78, GMBP1 disrupts the MDR mechanism, potentially sensitizing cancer cells to chemotherapy drugs Gonadotropin-releasing hormone analogs (GnRHa): Gonadotropin-releasing hormone analogs (GnRHa) have also been shown to block GRP78 and prevent the proliferation of defective cells. This disruption of GRP78 function triggers apoptosis, or programmed cell death, in these cells. GnRHa holds promise as a therapeutic agent for cancers characterized by GRP78 dysregulation Pep42-taxol and Pep42-doxorubicin: In the case of highly metastatic human melanoma cells, pep42-taxol and pep42-doxorubicin conjugates have been developed. These conjugates specifically bind to GRP78, resulting in the death of GRP78-expressing cancer cells in vitro. By selectively targeting GRP78, these conjugates offer a potential strategy to combat metastatic melanoma WIFPWIQL peptide: Another peptide of interest is the WIFPWIQL peptide. This peptide binds to GRP78 on cancer cells, and when fused with SubA, it forms an effective anticancer drug. The WIFPWIQL peptide is responsible for recognizing and internalizing GRP78 into cancer cells, while SubA, a bacterial cytotoxin, exerts a toxic effect by cleaving GRP78 inside the cell, inducing apoptosis | (Wang et al. 2015; Weng et al. 2014; Ibrahim et al. 2019; Beddoe et al. 2010; Zhang et al. 2016a, b) |
Monoclonal Antibodies | α 2-macroglobulin: The interaction between activated α2-macroglobulin and GRP78 on the surface of human prostate cancer cells plays a significant role in stimulating cell proliferation. This binding activates signaling cascades within the cells. Specifically, the N-terminal portion of cell surface GRP78 is connected to α2-macroglobulin, triggering the activation of the Akt pathway. This activation, in turn, blocks apoptotic pathways and promotes cell growth. This mechanism highlights the involvement of GRP78 in prostate cancer cell proliferation Mouse Monoclonal Antibody C107 & C38: Mouse monoclonal antibodies C107 and C38 recognize the C-terminal region of murine GRP78, which is exposed on the cell membrane. Upon binding, these antibodies exert their effects on melanoma cells. Specifically, they suppress the Akt/PI3K proliferative pathway. By targeting the exposed C-terminal region of GRP78, these antibodies interfere with the signaling cascades that promote cell growth and proliferation, offering potential therapeutic applications in melanoma treatment The binding of activated α2-macroglobulin to GRP78 and the interaction between mouse monoclonal antibodies and GRP78 highlight the intricate involvement of GRP78 in signaling pathways and its potential as a therapeutic target. Further research is needed to explore the precise mechanisms and clinical applications of these interactions | |
Anti-GRP78 autoantibodies | Anti-GRP78 autoantibodies have emerged as potential therapeutic agents for targeting cell surface GRP78 in various diseases, including cancer. The groundbreaking work by Wadih Arap and Renata Pasqualini, initially conducted at the University of Texas MD Anderson Cancer Center, played a pivotal role in identifying these autoantibodies in patients with cancer. In their original study published in the Proceedings of the National Academy of Sciences in 1998, titled "Phage display selection of ligand peptides targeting atherosclerotic lesions," Arap and Pasqualini employed phage display technology to identify peptides that specifically bound to atherosclerotic lesions in mice. Although this study primarily focused on atherosclerosis, it set the stage for subsequent investigations into the role of cell surface GRP78 and anti-GRP78 autoantibodies in cancer. Subsequently, Arap and Pasqualini continued their research at Rutgers University, delving deeper into the significance of anti-GRP78 autoantibodies in cancer. They discovered that certain autoantibodies targeted the N-terminal region of cell surface GRP78 and exhibited an unexpected effect by accelerating tumor growth. These autoantibodies appeared to enhance tumor cell survival and invasiveness by activating signaling pathways that promoted angiogenesis and immune evasion. Simultaneously, Arap and Pasqualini's research also revealed the presence of C-terminal anti-GRP78 autoantibodies in cancer patients. Unlike the N-terminal autoantibodies, these C-terminal autoantibodies exhibited tumor growth inhibitory effects. They were shown to block the growth of tumor cells and induce cell death, suggesting their potential as therapeutic agents for targeting cell surface GRP78 in cancer treatment. The identification of anti-GRP78 autoantibodies by Arap and Pasqualini provided a valuable insight into the complex role of cell surface GRP78 in cancer progression. These autoantibodies, particularly the C-terminal variants, demonstrated the therapeutic potential of targeting cell surface GRP78. By blocking the growth-promoting activities of GRP78 and inducing tumor cell death, they offered a novel strategy for combating cancer. The pioneering studies conducted by Arap and Pasqualini not only identified anti-GRP78 autoantibodies in cancer patients but also provided a foundation for subsequent investigations into the functional implications of these autoantibodies. Their work sparked further research by numerous scientists and research groups to explore the therapeutic potential of targeting cell surface GRP78 in cancer and other diseases Recent studies published in JCI Insight by Crane et al. highlighted the role of anti-GRP78 autoantibodies in promoting atherosclerosis. These autoantibodies were found to bind to cell surface GRP78 on endothelial cells within atherosclerotic lesions, leading to the activation of inflammatory and pro-atherogenic signaling pathways. The research demonstrated that targeting cell surface GRP78 or interfering with the binding of autoantibodies to GRP78 could attenuate atherosclerotic lesion formation, suggesting potential therapeutic avenues for treating cardiovascular diseases The seminal studies by Arap and Pasqualini, as well as subsequent investigations by the Pizzo and Gonzalez-Gronow group at Duke and the Al-Hashimi group at McMaster, have deepened our understanding of the functional significance of cell surface GRP78 and its potential as a therapeutic target in various diseases. Ongoing research continues to uncover the complex mechanisms underlying cell surface GRP78's roles in disease progression and explore its therapeutic implications | (Crane et al. 2018; Lebeau et al. 2021; Al-Hashimi et al. 2017; Mintz et al. 2003; Arap et al. 2004; Sato et al. 2010a; D’Angelo et al. 2018) |