Development of a novel prostate apoptosis response-4 (Par-4) protein entity with an extended duration of action for therapeutic treatment of cancer

Kim, Kyung‐Bo; Araujo, Nathalia; Hebbar, Nikhil; Zhou, Ziyuan; Zheng, Xirong; Zheng, Fang; Zhan, Chang‐Guo

doi:10.1093/protein/gzz034

Cited by 7 publications

(3 citation statements)

References 43 publications

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“…Por lo tanto, la proteína Par-4 puede ser una buena propuesta terapéutica contra diferentes tipos de cáncer (69)(70)(71), como el cáncer de mama agresivo (HER-2 positivo o triple negativo), por su capacidad de inducir apoptosis selectivamente en células cancerígenas, su capacidad de quimio sensibilizar y bloquear o revertir los procesos de recurrencia y metástasis a través de la sobreexpresión de la proteína con plásmidos o vectores virales, así como la inducción de Par-4 soluble por secretagogos (72,73).…”

Section: Par-4 En La Transición Epitelial a Mesenquimalunclassified

Papel de Par-4 en tumores de cáncer de mama en etapas tardías y recurrentes

2023

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ntroducción. Las muertes en los pacientes con cáncer de mama ocurren principalmente por la recurrencia y metástasis y no por el tumor primario, la agresividad del tumor se asocia al estatus hormonal, tumores receptor estrógeno negativo o triple negativo son neoplasias de mal pronóstico que tienen la capacidad de inducir metástasis o recurrencia la baja expresión de Par-4 se asocia a un mal pronóstico, por esa razón analizamos la participación de Par-4 en la recurrencia tumoral. Área cubierta. Se realizo una búsqueda de artículos relacionades con cáncer de mama, recurrencia y Par-4 en el PubMed y en otros bancos de datos, con la finalidad de comprender la relación de Par-4 como gen supresor de tumor con el proceso carcinogénico y recurrencia de cáncer de mama. Opinión experta. La baja expresión Par-4 está asociado en tumores receptor de estrógeno negativo o con alto grado de transformación, la expresión de par-4 disminuye o es bloqueada en las células remantes después de la quimioterapia y durante el proceso de transición epitelial mesenquimal (EMT) en la recurrencia del tumor, observándose que ar-4 es necesaria y esencial para la recurrencia del cáncer de mama. El entendimiento de la biología del Par-4 en el cáncer de mama abre la posibilidad de ser empleado como una estrategia terapéutica para que coadyuven a la eliminación destrucción de los tumores resistentes o recurrentes de cáncer de mama.

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Section: Par-4 En La Transición Epitelial a Mesenquimalunclassified

Papel de Par-4 en tumores de cáncer de mama en etapas tardías y recurrentes

2023

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“…Very recently, Kim et al developed a novel long-lasting form of Par-4 (Par-4Ex) by using E. coli expression system. Par-4Ex improved the biological half-life in mice by ~7-fold and effectively suppressed the metastatic tumor growth 115 . The evidence that Par-4 is important for cell death in many cancer cell types is mounting.…”

Section: Par-4 In Cancer Therapeutics: Its Brighter On the Other Sidementioning

confidence: 99%

Prostate apoptosis response-4 and tumor suppression: it’s not just about apoptosis anymore

et al. 2021

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The tumor suppressor prostate apoptosis response-4 (Par-4) has recently turned ‘twenty-five’. Beyond its indisputable role as an apoptosis inducer, an increasing and sometimes bewildering, new roles for Par-4 are being reported. These roles include its ability to regulate autophagy, senescence, and metastasis. This growing range of responses to Par-4 is reflected by our increasing understanding of the various mechanisms through which Par-4 can function. In this review, we summarize the existing knowledge on Par-4 tumor suppressive mechanisms, and discuss how the interaction of Par-4 with different regulators influence cell fate. This review also highlights the new secretory pathway that has emerged and the likely discussion on its clinical implications.

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“…The increase of Par-4 in the extracellular matrix causes cell death of tumor cells through binding to the overexpressing GRP78 receptor on the cell surface. Normal lines exhibit undetectable-to-low levels of this receptor [ 89 ], which protect them from the “friendly fire” though Par-4 is secreted by both normal and cancer tissues [ 89 , 90 ]. Therefore, Par-4 secretion is not associated with apoptosis and does not affect autophagy in normal mouse embryonic fibroblasts.…”

Section: Main Textmentioning

confidence: 99%

Aminoquinolines as Translational Models for Drug Repurposing: Anticancer Adjuvant Properties and Toxicokinetic-Related Features

Ferreira

Ferreira²,

Sousa

et al. 2021

Journal of Oncology

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The indiscriminate consumption of antimalarials against coronavirus disease-2019 emphasizes the longstanding clinical weapons of medicines. In this work, we conducted a review on the antitumor mechanisms of aminoquinolines, focusing on the responses and differences of tumor histological tissues and toxicity related to pharmacokinetics. This well-defined analysis shows similar mechanistic forms triggered by aminoquinolines in different histological tumor tissues and under coexposure conditions, although different pharmacological potencies also occur. These molecules are lysosomotropic amines that increase the antiproliferative action of chemotherapeutic agents, mainly by cell cycle arrest, histone acetylation, physiological changes in tyrosine kinase metabolism, inhibition of PI3K/Akt/mTOR pathways, cyclin D1, E2F1, angiogenesis, ribosome biogenesis, triggering of ATM-ATR/p53/p21 signaling, apoptosis, and presentation of tumor peptides. Their chemo/radiotherapy sensitization effects may be an adjuvant option against solid tumors, since 4-aminoquinolines induce lysosomal-mediated programmed cytotoxicity of cancer cells and accumulation of key markers, predominantly, LAMP1, p62/SQSTM1, LC3 members, GAPDH, beclin-1/Atg6, α-synuclein, and granules of lipofuscin. Adverse effects are dose-dependent, though most common with chloroquine, hydroxychloroquine, amodiaquine, and other aminoquinolines are gastrointestinal changes, blurred vision ventricular arrhythmias, cardiac arrest, QTc prolongation, severe hypoglycemia with loss of consciousness, and retinopathy, and they are more common with chloroquine than with hydroxychloroquine and amodiaquine due to pharmacokinetic features. Additionally, psychological/neurological effects were also detected during acute or chronic use, but aminoquinolines do not cross the placenta easily and low quantity is found in breast milk despite their long mean residence times, which depends on the coexistence of hepatic diseases (cancer-related or not), first pass metabolism, and comedications. The low cost and availability on the world market have converted aminoquinolines into “star drugs” for pharmaceutical repurposing, but a continuous pharmacovigilance is necessary because these antimalarials have multiple modes of action/unwanted targets, relatively narrow therapeutic windows, recurrent adverse effects, and related poisoning self-treatment. Therefore, their use must obey strict rules, ethical and medical prescriptions, and clinical and laboratory monitoring.

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Development of a novel prostate apoptosis response-4 (Par-4) protein entity with an extended duration of action for therapeutic treatment of cancer

Cited by 7 publications

References 43 publications

Papel de Par-4 en tumores de cáncer de mama en etapas tardías y recurrentes

Papel de Par-4 en tumores de cáncer de mama en etapas tardías y recurrentes

Prostate apoptosis response-4 and tumor suppression: it’s not just about apoptosis anymore

Aminoquinolines as Translational Models for Drug Repurposing: Anticancer Adjuvant Properties and Toxicokinetic-Related Features

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