Table 3 Small molecules or endogenous molecules with promising cytotoxic effect on melanoma through regulated cell death pathway other than apoptosis

Autophagy dependent cell death

HydroxyCQ

Blocking of autophagosmoe fusion with lysosome; augmented temozolomide-induced melanoma cell death

C8161 melanoma spheroid

[55]

7-hydroxydehydronuciferine

Cytotoxic to melanoma cell

A375.S2, A375 and A2058 melanoma cell; A375.S2 cells in mouse model

[57]

4-PBA

Reduction of ER stress and basal autophagy; susceptibility to apoptosis induction

SK-Mel-110  BRAF ^V600E cell

[51]

Pyroptosis

Doxorubicin, cisplatin, actinomycin-D, topotecan, CPT-11, etoposide and mitoxantrone

Pyroptosis induction through GSDME cleavage

GSDME ( +) SH-SY5Y neuroblastoma and MeWo skin melanoma cell

[71]

Etoposide

Reinduction of GDEME cleavage and pyroptosis after resistance development to PLX4720 (BRAFi) and PD0325901 (MEKi)

YUMM1.7 cell from combination resistant tumor (CRT), in mouse model

[74]

GSK2334470 and trametinib

PDPK1 and MEK inhibition to induce GSDME mediated pyroptosis, increased CD8 + T cells in tumor

WM1361A, WM1366, SK- -30 and SK -MEL-173 cell (all NRAS mutant), in mouse model

[76]

Iron dextran

Iron-activated ROS via a Tom 20-Bax-caspase 3- GSDME pathway

A375 melanoma cell in mouse model

[77]

Raptinal (caspase 3 activator)

Induction of pyroptosis and delay the growth of BRAFi and MEKi-resistant tumor cells in vivo

Human A375, WM35 and mouse D4M3.A and YUMM1.7 melanoma cell; YUMM1.7 and CRT47R cell in mouse model

[83]

Temozolomide and chloroquine

Autophagy inhibition and inflammasome activation after development of BRAF inhibitor resistance

Melanoma cell from patients receiving BRAFi (vemurafenib), in mouse model

[75]

Necroptosis

Curaxin CBL0137

To trigger Z-DNA formation in melanoma-infiltrating fibroblasts to induce ZBP1-dependent necroptosis

Immune checkpoint blockade non-responsiveness mouse model (B16-F10 melanoma in Zbp1^−/− mouse)

[96]

GNE684

Inhibition of cross-species RIPK1; RIPK1 inhibition by GNE684 or knock-in of Ripk1^D138N/D138N did not affect B16 metastasis

B16-F10 cell in mouse model

[93]

N-TiO₂

Impaired autophagosome -lysosome fusion, the blockade of autophagy flux via ROS production after photoactivation

A375 melanoma cell

[88]

PK68

RIPK1 inhibition and repression of melanoma metastasis

B16-F10 cell in mouse model

[92]

Necroptosis, ferroptosis

BAY 87–2243

Mitochondrial complex I inhibition to increase ROS; reduced cell death by necrostatin/ knockdown of RIPK1 or MLKL; also ferrostatin/ knockdown of GPX4

Human G361 and SK-MEL-28 melanoma cell

[97]

Ferroptosis

Biomineralized nanovaccine with Fe⁺³ and photosensitizer IR820

Increase ROS and lipid peroxide, decreased GSH level, GPX4 inhibition, augmented anti-CTLA4 antibody efficiency

B16-OVA cell, in mouse model

[114]

Nobiletin

GSK3β-mediated Keap1/Nrf2/HO-1 signaling pathway

SK-MEL-28 melanoma cell

[108]

Phyto-sesquiterpene lactone, DET, and DETD-35

Lipid ROS accumulation, GPX4 inhibition

A375, A2058 and SK-MEL-2 melanoma cell, PLX4032 (vemurafenib) resistant A375 cell

[109]

Not sure, possible cuproptosis

Elesclomol

Elimination of the slow-cycling melanoma cell under the treatment of cytotoxic drugs (cisplatin)

JARID1B^high

WM3734 melanoma cell

[134]

Autophagy dependent cell death

CCL5

Increased CCL5 expression in BECN1- melanoma, CCL5- dependent increased infiltration of NK cells to the tumor

BECN- B16-F10 melanoma cell in mouse model

[61, 62]

MAP1LC3B

Restoration to killing by tumor-reactive T cells by this autophagy initiator

Human PTEN-silenced melanoma cell

[59]

miR-216b

Ectopic expression increases the efficacy of vemurafenib both in vitro and in vivo

A375 and A375-

vemurafenib-

resistant cell, in mouse model

[56]

Pyroptosis

DNA vaccine consisting of plasmids encoding caspase-1 and an ovalbumin- derived CD8 T cell epitope

GSDMD dependent cell death, amplified antigen-specific CD8 T cell responses and longer survival

HEK-293 cell line, B16-OVA melanoma cell in C57BL/6 mouse model

[82]

Necroptosis

Tumor delivery of MLKL mRNA

Inhibition of primary and distant melanoma growth; augmented antitumor activity with immune checkpoint blockade therapy

B16-OVA melanoma cell in C57BL/6 mouse model

[95]

Ferroptosis

miR-21-3p-loaded gold nanoparticles

Enhance lipid ROS generation and ferroptosis promotion; synergistic with anti-PD-1 antibody to promote ferroptosis

A375, A2058 melanoma cell;

B16-F10 cell in mouse model

[113]