A Gallium(III) Complex that Engages Protein Disulfide Isomerase A3 (PDIA3) as an Anticancer Target

Yin, Hao‐Yan; Gao, Jiu‐Jiao; Chen, Xuemin; Ma, Bin; Yang, Zi‐Shu; Tang, Juan; Wang, Bing‐Wu; Chen, Tianfeng; Wang, Chu; Gao, Song; Zhang, Junlong

doi:10.1002/anie.202008432

Cited by 39 publications

(40 citation statements)

References 66 publications

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“…Most PDI inhibitors are known to or likely to bind to catalytic sites of the a or a' domain of PDI: they include PACMA31 [114], P1 [115], 16F16 [116], AS15 [117], CCF642 [118], S-CW3554 [119], Origamicin [120], (±)-dMtcyDTDO [121], Ga-1 [122], 35G8 [123], Copper (II) complex 1 [124], and SK053 [125]. PACMA31 belongs to the class of propynoic acid carbamoyl methyl amides (PACMAs), and it covalently binds to the Cys400 of the active site of PDI, and it shows cytotoxicity on a broad range of human cancer cells [81].…”

Section: Pdi Inhibitors Categorized Depending On Binding Sitesmentioning

confidence: 99%

“…It seems to interact with PDIA1, but its binding site on PDIA1 has not yet been determined. A Gallium (III) complex, Ga-1, is a metal-based PDI inhibitor and most likely interacts with active site His55 of PDIA3 with the cyanic group [122]. In addition to PDIA3, three other isoforms such as PDIA1, PDIA4, and PDIA6 are determined for Ga-1 to bind.…”

Section: Pdi Inhibitors Categorized Depending On Binding Sitesmentioning

confidence: 99%

“…Ga-1 is a gallium (III) based compound that shows stronger anticancer activity compared to cisplatin in breast cancer cells (MCF-7) with an IC50 of 0.42 μM [122]. Previously, the antitumor effects of Ga (III)-based compounds were considered to be iron-dependent, disrupting cellular iron homeostasis and metabolism [149].…”

mentioning

confidence: 99%

“…However, Ga-1 is proved to induce ER stress, mitochondria dysfunction, and subsequent cell death in cancer cells. Treatment with Ga-1 increases the ratio of phosphorylated eIF2α to the total eIF2α, up-regulates ATF4 and CHOP, activates the mitogen-activated protein kinases (MAPK) signaling pathway, and upregulates Bax and downregulates Bcl-2 [122]. Also, Ga-1 induced mitochondria dysfunction, including disruption of mitochondria membrane permeability, could be explained by the observation that Ga-1 increases the reactive oxygen species (ROS) level, induces morphological changes of mitochondria, and decreases mitochondria membrane potential (MMP) [122].…”

mentioning

confidence: 99%

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Roles of Protein Disulfide Isomerase in Breast Cancer

Yang

Jackson

Karapetyan

et al. 2022

Cancers

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Protein disulfide isomerase (PDI) is the endoplasmic reticulum (ER)’s most abundant and essential enzyme and serves as the primary catalyst for protein folding. Due to its apparent role in supporting the rapid proliferation of cancer cells, the selective blockade of PDI results in apoptosis through sustained activation of UPR pathways. The functions of PDI, especially in cancers, have been extensively studied over a decade, and recent research has explored the use of PDI inhibitors in the treatment of cancers but with focus areas of other cancers, such as brain or ovarian cancer. In this review, we discuss the roles of PDI members in breast cancer and PDI inhibitors used in breast cancer research. Additionally, a few PDI members may be suggested as potential molecular targets for highly metastatic breast cancers, such as TNBC, that require more attention in future research.

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Section: Pdi Inhibitors Categorized Depending On Binding Sitesmentioning

confidence: 99%

Section: Pdi Inhibitors Categorized Depending On Binding Sitesmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Roles of Protein Disulfide Isomerase in Breast Cancer

Yang

Jackson

Karapetyan

et al. 2022

Cancers

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“…2,3 Recently, other metal-based compounds with potential anti-cancer properties have been reported. 4,5 Ruthenium compounds are a potential alternative to platinum-based drugs due to their chemical and pharmacological properties. A number of ruthenium-based complexes have been reported to have promising anticancer activity, four of which have entered clinical trials.…”

Section: Introductionmentioning

confidence: 99%

A New Pyrazolate Osmium(VI) Nitrido Complex Exhibits Anticancer Activity Through Modulating Protein Homeostasis

Ni¹,

Huang²,

Huang³

et al. 2020

Preprint

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Interest in the third-row transition metal osmium and its compounds as potential anticancer agents has grown in recent years. Here, we synthesized the osmium(VI) nitrido complex Na[OsVI(N)(tpm)2] (tpm= [5-(Thien-2-yl)-1H-pyrazol-3-yl]methanol) that does not have direct binding affinity to DNA. Cellular assays revealed that this new Os complex exhibited anticancer activity against cancer cell lines, cancer stem cells, and cisplatin-resistant cells. The Os complex Na[OsVI(N)(tpm)2] modulates the expression of protein transportation-associated, DNA metabolism-associated and oxidative stress-associated proteins in HepG2 cells. Perturbation of protein expression activity by the Os complex in cancer cells affects the functions of the mitochondria and endoplasmic reticulum, resulting in high levels of cellular oxidative stress and low rates of cell survival. Moreover, it induced caspase-mediated apoptosis of HepG2 cancer cells. The study reveals a new high-valent Os complex as an anticancer agent candidate targeting cancer cell protein homeostasis.

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Biomimetic MOF‐Based Nano‐Immunoactivator via Disruption of Ion Homeostasis for Strengthened Tumor Microwave‐Immunotherapy

Chen,

Guo,

Tan

et al. 2024

Adv Funct Materials

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Immunogenic cell death (ICD) is a promising strategy for anticancer immunity by inducing antigen‐presenting cell maturation. However, the traditional ICD inducers, such as chemotherapeutic agents, have largely hampered their application by severe side effects and low tumor selectivity. The changes intra/extracellular ion concentrations affect the growth and metastasis of tumor cells. Interference with ion homeostasis can induce tumor cell death and elicit immune responses. Here, a biomimetic Ga‐based metal–organic framework (MOF) coated with red blood cell–platelet fusion membrane (RPM), that is, 5‐fluorouracil@GaMOF@RPM (5‐FUGR) nano‐immunoactivator, is reported as a highly efficient ICD inducer for enhanced microwave (MW)‐immunotherapy. Following intravenous administration, 5‐FUGR accumulates to tumor site via RPM biomimetic modification‐mediated long circulation and active targeting. The structure of 5‐FUGR undergoes degradation and releases Ga3+. MW combined with high concentrations of Ga3+ disrupts intracellular ion homeostasis, which leads to severe oxidative stress and intracellular Ca2+ retention to promote apoptosis of tumor cells. More importantly, 5‐FUGR combined with MW not only completely eradicates 4T1 primary tumors, but also induces efficient ICD, immune initiation, and memory effects to inhibit metastatic and recurrence of the tumor. Thus, 5‐FUGR, as a strong ICD inducer, provides new insights into achieving tumor immunity in combination with other therapies.

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A Gallium(III) Complex that Engages Protein Disulfide Isomerase A3 (PDIA3) as an Anticancer Target

Cited by 39 publications

References 66 publications

Roles of Protein Disulfide Isomerase in Breast Cancer

Roles of Protein Disulfide Isomerase in Breast Cancer

A New Pyrazolate Osmium(VI) Nitrido Complex Exhibits Anticancer Activity Through Modulating Protein Homeostasis

Biomimetic MOF‐Based Nano‐Immunoactivator via Disruption of Ion Homeostasis for Strengthened Tumor Microwave‐Immunotherapy

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