ArticleApoptosis : an international journal on programmed cell death2012
D-Penicillamine targets metastatic melanoma cells with induction of the unfolded protein response (UPR) and Noxa (PMAIP1)-dependent mitochondrial apoptosis.
Article in Apoptosis : an international journal on programmed cell death, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
19 citing papers in PubMed, 35 citations in OpenAlex.
- Magnesium isoglycyrrhizinate ameliorates acetaminophen-induced acute liver injury with hyperglycaemia by modulating autophagy and oxidative stress in liver-resident macrophages.Frontiers in pharmacology · 2026Article
- Integrated single-cell and machine learning analysis identifies PMAIP1 as a novel biomarker for predicting prognosis and immunotherapy response in colorectal cancer.Scientific reports · 2025Article
- Copper Homeostasis, Emerging Central Players in Cancer Immunotherapy.Journal of cellular and molecular medicine · 2025Review
- Iron, copper and disulfide dysregulation: molecular crossroads of metabolic cell death in melanoma progression.Frontiers in pharmacology · 2025Review
- Copper and Colorectal Cancer.Cancers · 2024Review
- Evolving approaches in glioma treatment: harnessing the potential of copper metabolism modulation.RSC advances · 2023Review
- Copper metabolism in cell death and autophagy.Autophagy · 2023Review
- Mefloquine induces ER stress and apoptosis in BRAFi-resistant A375-BRAFMolecular carcinogenesis · 2022Article
- Modulation of Intracellular Copper Levels as the Mechanism of Action of Anticancer Copper Complexes: Clinical Relevance.Biomedicines · 2021Review
- Pigmentation Levels Affect Melanoma Responses toInternational journal of molecular sciences · 2021Article
- Article
- D-penicillamine combined with inhibitors of hydroperoxide metabolism enhances lung and breast cancer cell responses to radiation and carboplatin via HFree radical biology & medicine · 2017Article
- Reduction of Thrombosis and Bacterial Infection via Controlled Nitric Oxide (NO) Release fromACS biomaterials science & engineering · 2017Article
- Melanoma and the Unfolded Protein Response.Cancers · 2016Review
- Protective Effects of D-Penicillamine on Catecholamine-Induced Myocardial Injury.Oxidative medicine and cellular longevity · 2016Article
- The quinone methide aurin is a heat shock response inducer that causes proteotoxic stress and Noxa-dependent apoptosis in malignant melanoma cells.The Journal of biological chemistry · 2015Article
- Cancer Microenvironment and Endoplasmic Reticulum Stress Response.Mediators of inflammation · 2015Review
- Article
- The role of endoplasmic reticulum stress in maintaining and targeting multiple myeloma: a double-edged sword of adaptation and apoptosis.Frontiers in genetics · 2013Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
D-Penicillamine (3,3-dimethyl-D-cysteine; DP) is an FDA-approved redox-active D-cysteine-derivative with antioxidant, disulfide-reducing, and metal chelating properties used therapeutically for the control of copper-related pathology in Wilson's disease and reductive cystine-solubilization in cystinuria. Based on the established sensitivity of metastatic melanoma cells to pharmacological modulation of cellular oxidative stress, we tested feasibility of using DP for chemotherapeutic intervention targeting human A375 melanoma cells in vitro and in vivo. DP treatment induced caspase-dependent cell death in cultured human metastatic melanoma cells (A375, G361) without compromising viability of primary epidermal melanocytes, an effect not observed with the thiol-antioxidants N-acetyl-L-cysteine (NAC) and dithiothreitol. Focused gene expression array analysis followed by immunoblot detection revealed that DP rapidly activates the cytotoxic unfolded protein response (UPR; involving phospho-PERK, phospho-eIF2α, Grp78, CHOP, and Hsp70) and the mitochondrial pathway of apoptosis with p53 upregulation and modulation of Bcl-2 family members (involving Noxa, Mcl-1, and Bcl-2). DP (but not NAC) induced oxidative stress with early impairment of glutathione homeostasis and mitochondrial transmembrane potential. SiRNA-based antagonism of PMAIP1 expression blocked DP-induced upregulation of the proapoptotic BH3-only effector Noxa and prevented downregulation of the Noxa-antagonist Mcl-1, rescuing melanoma cells from DP-induced apoptosis. Intraperitoneal administration of DP displayed significant antimelanoma activity in a murine A375 xenograft model. It remains to be seen if melanoma cell-directed induction of UPR and apoptosis using DP or improved DP-derivatives can be harnessed for future chemotherapeutic intervention.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.