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Table 1 Summary of agents targeting novel RCDs in cancer-related preclinical studies

From: Targeting cell death pathways for cancer therapy: recent developments in necroptosis, pyroptosis, ferroptosis, and cuproptosis research

Classification

Compound

Cell death pathways

Mechanisms

Cancer type

References

Small compound

Shikonin

Necroptosis induction

Increases ROS production and upregulates RIPK1, RIPK3, and MLKL

Nasopharyngeal carcinoma

[227]

FDA-approved drug

FTY720

Necroptosis induction

Targets I2PP2A/SET and activates PP2A/RIPK1

Lung cancer

[228]

NPs

Graphene oxide NPs

Necroptosis induction

Increases the activity of RIPK1, RIPK3, and HMGB1

Colon cancer

[229]

NPs

Selenium NPs

Necroptosis induction

Increases ROS and RIPK1 production

Prostate adenocarcinoma cells

[230]

Small compound

Emodin

Necroptosis induction

Enhances TNF/RIPK1/RIPK3 signaling

Glioma

[231]

Small compound

Ophiopogonin D′

Necroptosis induction

Upregulates RIPK1

Prostate cancer

[232]

Small compound

Resibufogenin

Necroptosis induction

Upregulates RIPK3

CRC

[104]

Small compound

Bufalin

Necroptosis induction

Upregulates RIPK1/RIPK3

Breast cancer

[233]

Small compound

Tanshinol A

Necroptosis induction

Increases intracellular ROS and MLKL levels

Lung cancer

[234]

FDA-approved drug

Chloroquine (CQ)

Necroptosis induction

Upregulates RIPK3

CRC

[235]

NPs

Hyaluronic acid -modified, lipid-coated PLGA NPs loaded with mRIP3-pDNA

Necroptosis induction

Upregulates RIPK3

CRC, breast cancer, melanoma

[235]

Small compound

CBL0137

Necroptosis induction

Activate ZBP1

Liver cancer, breast cancer, colorectal cancer, cervical cancer, melanoma

[236]

Small compound

Smac mimetics

Necroptosis induction

Antagonizes inhibitor of apoptosis proteins (cIAPs)

Burkitt’s lymphoma

[237]

NPs

Fe(III)-shikonin supramolecular nanomedicine (FSSN)

Necroptosis/ferroptosis induction

1. Decreases GSH levels

2. Promotes RIPK1-RIPK3 complex generation

Breast cancer

[238]

Small compound

Necrosulfonamide (NSA)

Necroptosis inhibition

1. Inhibits MLKL

Breast cancer

[110]

Small compound

PK68

Necroptosis inhibition

1. Inhibits RIPK1

Melanoma, lung carcinoma cells

[239]

Small compound

Necrostatin-1

Necroptosis inhibition

1. Inhibits RIPK1

Colitis-associated CRC

[240]

FDA-approved drug

Metformin

Pyroptosis induction

1. Induces GSDMD-mediated pyroptosis by targeting the miR-497-PELP1 axis

2. Causes mitochondrial dysfunction and activates the AMPK/sirtuin1/NF-κB pathway

Breast cancer, esophageal squamous cell carcinoma

[241, 242]

Small compound

Tetraarsenic hexoxide

Pyroptosis induction

Enhance the production of mitochondrial reactive oxygen species (ROS) by inhibiting phosphorylation STAT3

Breast cancer

[243]

FDA-approved drug

Docosahexaenoic acid

Pyroptosis induction

Increases caspase-1 levels and activates GSDMD

Breast cancer

[244]

Small compound

Polyphyllin VI

Pyroptosis induction

Increases ROS production

NSCLC

[245, 246]

FDA-approved drug

Simvastatin

Pyroptosis induction

Increases caspase-1 expression

NSCLC

[118]

Small compound

Galangin

Pyroptosis induction

Increases levels of the GSDME N-terminus

Glioblastoma multiforme

[247]

Investigational drug

Lobaplatin

Pyroptosis induction

Induces ROS production and JNK phosphorylation

Colon cancer

[248]

Investigational + FDA-approved drugs

Mirdametinib + Vemurafenib

Pyroptosis induction

Inhibits the MEK/ERK 1/2 pathway and promotes Bim/Bmf-mediated mitochondrial depolarization

Melanoma

[182]

Small compound

Miltirone

Pyroptosis induction

Inhibits the MEK/ERK 1/2 pathway and promotes ROS accumulation

Hepatocellular carcinoma

[249]

NPs

Biomimetic nanoparticles

Pyroptosis induction

Induces the mitochondrial damage and activates caspase-3

Breast cancer

[250]

NPs

DAC + LipoDDP

Pyroptosis induction

Activates the caspase-3 pathway

Breast cancer

[188]

NPs

Synthetic RIG-I agonist

Pyroptosis induction

Activates STAT1 and NF-κB

Breast cancer

[251]

NPs

CXCR4-targeted NPs

Pyroptosis induction

Upregulates caspase-11 and NLPR3 expression

Colorectal cancer

[252]

NPs

Lip MOF NPs

Pyroptosis induction

Cleaves GSDMD and increases IL-1β levels

Cervical cancer

[253]

NPs

Arsenic trioxide NPs

Pyroptosis induction

Increases caspase-3 expression

Hepatocellular carcinoma

[254]

NPs

ROS-responsive polyion complex

Pyroptosis induction

Induces oxidative DNA damage

Breast cancer

[255]

FDA-approved drug

Paclitaxel

Pyroptosis induction

Activates caspase-3/GSDME

Lung cancer

[256]

Small compound

Anthocyanin

Pyroptosis induction

Increases caspase-1 levels

Oral squamous cell carcinoma

[257]

Small compound

JQ-1

Pyroptosis induction

Activates the NF-κB-NLRP3-caspase-1 pathway

Renal cell carcinoma

[258]

Investigational drug

Talabostat

Pyroptosis induction

Activates caspase-1

Cervical cancer, fibrosarcoma, breast cancer

[213]

Small compound

Ivermectin

Pyroptosis induction

Activates P2X4/P2X7-gated pannexin-1 channel

Breast cancer

[259]

Small compound

Ophiopogonin B

Pyroptosis induction

Activates caspase-1/GSDMD pathway

Lung cancer

[260]

Small compound

GW4064

Pyroptosis induction

Activates caspase-3/GSDME pathway

CRC

[261]

FDA-approved drug

Doxorubicin

Ferroptosis/pyroptosis induction

Increases lipid ROS levels

HCC, CRC

[262, 263]

Investigational drug

Anti-GSDMB antibody

Pyroptosis inhibition

Inhibits GSDMB

Breast cancer

[264]

Small compound

Dimethyl fumarate

Pyroptosis inhibition

Inhibits GSDMD

Breast cancer

[265]

NPs

Zero-valent iron NPs

Ferroptosis induction

Converts zero-valent iron to Fe(II) and facilitates Fenton reactions

Oral cancer

[266]

NPs

Fe-CO@Mito-PNBE

Ferroptosis induction

(1) Enhances ROS generation

(2) Releases Fe(III)/Fe(II) ions in the TME and triggers the Fenton reaction

Cervical cancer, breast cancer

[267]

Small compound

IMCA

Ferroptosis induction

Downregulates SLC7A11 expression and reduces cellular cysteine uptake

Colorectal cancer

[268]

Small compound

Imidazole ketone erastin

Ferroptosis induction

Inhibits system XC−

Diffuse large B cell lymphoma

[269]

Small compound

Hydrolysis product 4 of open chain epothilone analogs

Ferroptosis induction

Inhibits system XC−

Fibrosarcoma, rhabdomyosarcoma

[270]

Small compound

ML210

Ferroptosis induction

Suppresses GPX4

Melanoma, pancreatic cancer, lung adenocarcinoma, fibrosarcoma, renal cell carcinoma, pancreatic cancer

[271]

Small compound

ML162

Ferroptosis induction

Suppresses GPX4

Fibrosarcoma

[59]

Small compound

DMOCPTL

Ferroptosis induction

Suppresses GPX4

Breast cancer

[272]

Small compound

FIN56

Ferroptosis induction

Inhibits CoQ10 biosynthesis

Fibrosarcoma

[273]

Small compound

FINO2

Ferroptosis induction

Suppresses GPX4

Fibrosarcoma

[274]

Small compound

Albiziabioside A derivative

Ferroptosis induction

Suppresses GPX4

CRC

[275]

Small compound

Trigonelline

Ferroptosis induction

Decreases GSH levels

Head and neck cancer cells

[276]

FDA-approved drug

Glutamate

Ferroptosis induction

Inhibits system XC−

Fibrosarcoma

[56]

NPs

MFC-Gem

Ferroptosis induction

Decrease GSH levels

Pancreatic cancer

[277]

Small compound

Erianin

Ferroptosis induction

Activates Ca2+/CaM signaling

Lung cancer

[278]

FDA-approved drug

Etoposide

Ferroptosis induction

Decreases GPX4 levels

Myelogenous leukemia

[279]

NPs

FePt/MoS2 nanocomposites

Ferroptosis induction

Supplies Fe(II) and accelerates Fenton reactions

Cervical carcinoma, breast cancer

[280]

FDA-approved drug

Sorafenib

Ferroptosis induction

Inhibits cystine–glutamate antiporter (system XC−)

Fibrosarcoma, Ewing’s sarcoma, lung cancer, osteosarcoma

[281]

Investigational drug + FDA-approved drug

Siramesine + lapatinib

Ferroptosis induction

Inhibits ferroportin-1

Breast cancer

[282]

FDA-approved drug

Cisplatin

Ferroptosis induction

Depletes glutathione (GSH) and inactivates GPX4

NSCLC, colon cancer

[197]

FDA-approved drug

Decitabine

Ferroptosis induction

Decreases GSH levels and inhibits GPX4 activity

Myelodysplastic syndrome

[283]

Synthetic exosomes

Erastin@FA-exo

Ferroptosis induction

Suppresses GPX4 expression and upregulates cysteine dioxygenase

Breast cancer

[284]

FDA-approved drug

Apatinib

Ferroptosis induction

1. Inactivates GPX4

2. Upregulates ELOVL6/ACSL4

3. Inhibits the VEGFR2/Nrf2/Keap1 pathway

Gastric cancer, colorectal cancer, glioma

[285,286,287]

FDA-approved drug

Altretamine

Ferroptosis induction

Inactivates GPX4

Diffuse large B cell lymphoma

[288]

FDA-approved drug

Neratinib

Ferroptosis induction

Increases ferritin levels

Breast cancer

[289]

Investigational drug

APR-246

Ferroptosis induction

Decreases GSH biosynthesis

Acute myeloid leukemia

[290]

Investigational drug

Flubendazole

Ferroptosis induction

Inhibits SLC7A11 transcription

Prostate cancer

[291]

FDA-approved drug

Sulfasalazine

Ferroptosis induction

Inhibits system XC−

Head and neck cancer

[292]

FDA-approved drug

Statins

Ferroptosis induction

Inhibits CoQ10 biosynthesis

NSCLC

[293, 294]

FDA-approved drug

Dihydroartemisinin

Ferroptosis induction

Inhibits GPX4

Leukemia

[295, 296]

Small compound

RSL3

Ferroptosis induction

Suppresses GPX4

CRC

[297]

Small compound

MMRi62

Ferroptosis induction

Degrades mutant p53 and ferritin heavy chain

Pancreatic cancer

[298]

FDA-approved drug

Artesunate

Ferroptosis induction

Promotes ROS signaling and lipid peroxidation

Pancreatic cancer

[299]

Investigational drug

Buthionine sulfoximine

Ferroptosis/cuproptosis induction

Decreases GPX4 levels

Hepatocellular carcinoma, lung cancer

[140, 300]

Small compound

5-aminolevulinic acid

Ferroptosis induction

Inhibits GPX4 and increase heme oxygenase 1(HO-1)

Esophageal squamous cell carcinoma

[301]

Chinese patent medicine

Shuganning injection

Ferroptosis induction

Increases HO-1

Triple-negative breast cancer

[302]

Small compound

Trichothecin

Ferroptosis induction

Upregulates RIPK3

CRC, Burkitt lymphoma

[303]

NPs

ZVI-NP

Ferroptosis induction

Inactivates NRF2

Lung cancer

[194]

NPs

2,2,6,6, tetramethylpiperidine-N-oxyl capped TiO2 nanorods (TiO2 NRs) + radiotherapy

Ferroptosis inhibition

Induces GSH

Breast cancer

[304]

Small compound

Liproxstatin-1

Ferroptosis inhibition

Slow the accumulation of lipid hydroperoxides

Pancreatic cancer

[305]

Investigational drug

Elesclomol

Cuproptosis induction

1. Increases copper levels and targets lipoylated TCA cycle proteins

2. Targets copper-transporting ATPase 1 and regulates ferroptosis

NSCLC, lung adenocarcinoma, pancreatic cancer, papillary thyroid carcinoma, ovarian cancer, colorectal cancer

[25, 75]

NPs

CuET NPs

Cuproptosis induction

Reduces FDX1 expression

NSCLC

[306]