Table 1.

Evidence-based anticancer effects of prodigiosin

Cancer(s) type	Study model(s)	Anticancer effect(s)	Reference(s)
Ovarian	A2780RCIS (MRP1, 2 overexpressing cell line)	↓ Cell viability Acts regardless of the BCRP, MDR1, or MRP transporter	[40]
Gastric	EPG85-257RNOV EPG85-257RDB
	HGT-1 cell line	↑ Apoptosis ↓ Cell viability Cell shrinkage Cell detachment from the culture substrate	[41]
Glioblastoma	U87MG cell line GBM8401 cell line	Stimulates stress markers of ER (e.g., BiP/GRP78, CHOP, and sXBP1) ↑ Autophagic cell death Activates the JNK pathway ↓ Decreasing the AKT/mTOR pathway ↑ Caspase 3 levels ↑ PARP cleavage ↑ LC3-II/LC3-I ↑ Bax/β-Actin ratio ↓ p62	[42]
Neuroblastoma	LAN-1 IMR-2 SK-N-AS SH-SY5Y	Uncouples the protons of the ETC to mitochondrial ATP synthase ↓ ATP production	[43]
Colorectal cancer (CRC)	HT-29 cell line	↓ G2/M ↑ Blockage in the G1 phase ↓ Number of viable cells ↓ Survivin mRNA levels ↑ Caspase 3 levels ↑ Bax mRNA levels ↑ Bad mRNA levels ↑ P53 protein levels ↓ Bcl-2 mRNA levels	[44–46]
	DLD-1 cells SW-620 cells	↑ Apoptosis ↑ Caspases levels Acts irrespective of p53 status (mutant or absent) PARP cleavage	[47]
	DLD-1 cells	↑ P53 protein levels ↑ Apoptosis ↑ Lysosomal pH	[46]
	WiDr cells	↑ Anticancer activity	[48]
	NRK normal cells Swiss-3T3 normal cells	No significant decrease in viable cells No apoptosis No toxicity	[47]
	HCT116 cells SW480 cells HT-29 cells N87 cells AGS cells LoVo cells Nude BALB/c male mice	Accumulation of LC3B-II and SQSTM ↓ Lysosomal activity by accumulating EGFP-LC3 puncta Triggers autophagy ↑ LC3-II/LC3-I ↑ Caspase 3 levels ↑ in-vitro sensitivity to 5-FU ↑ in-vivo 5-FU efficacy	[49]
	SW480 cells HCT116 cells DLD1 cells Athymic nu/nu mice	Restores P53 Activates P73 Prevents formation of colonosphere irrespective of p53 ↓ Viability of self-renewing 5-fluorouracil-resistant Aldefluor( +) CRCSCs ↓ Growth of xenograft tumours initiated with Aldefluor( +) cells without toxic effects and limits their tumourigenesis Activates a p53-responsive luciferase reporter in colonospheres ↓ Levels of the oncogenic N-terminally truncated isoform ΔNp73 in Aldefluor( +) cells ↑ Levels of the transcription factor c-Jun	[50]
	P53 mutant SW480 cells	Rescues a deficient P53 pathway ↑ Antitumour effects via disruption of the mutant P53/P73 complex and P73 upregulation	[51]
Breast	T47D cell line	No effect on cell cycle ↑ Signature ER stress markers (i.e., CHOP and GRP78) ↑ Caspase 3 levels ↑ Bax expression levels ↑ Bak expression levels ↓ Bcl-2 expression levels ↓ Survivin transcription levels ↑ Apoptosis ↓ RAD51 mRNA expression ↑ JNK signalling pathway ↑ P38 MAPK signalling pathway	[44, 52–55]
	MCF-7 cell line	↑ Signature ER stress markers (i.e., CHOP and GRP78) ↑ Apoptosis ↓ RAD51 mRNA expression ↑ JNK signalling pathway ↑ P38 MAPK signalling pathway Activates the IRE1–JNK pathway Activation of GSK3β Accumulation of P53 protein ↑ Bak expression levels ↑ Caspase 3 levels ↑ Caspase 7 levels ↓ Bcl-2 expression levels ↓ Survivin transcription levels ↑ Bax expression levels Activates NAG-1 Activates the PERK–eIF2α pathway ↑ P53 protein levels ↑ PUMA protein levels Arrests cell cycle at G1 phase	[52–58]
	MDA-MB-231 cell line	↓ Bcl-2 transcription and expression levels ↓ Cell viability ↓ Proliferation ↓ Phosphorylated LRP6 ↓ Phosphorylated DVL2 ↑ Apoptosis ↑ Caspase 3 levels ↑ Caspase 8 levels ↑ Caspase 9 levels No effect on Raf-1 ↑ Bak expression levels ↓ Survivin transcription and expression levels ↓ HSP90ɑ mRNA and protein levels ↑ Bax mRNA levels ↓ RAD51 mRNA expression ↑ JNK signalling pathway ↑ P38 MAPK signalling pathway ↓ mTOR expression levels ↓ EGFR expression levels ↓ VEGF expression levels PARP cleavage Blocked Wnt/β-Catenin signalling ↓ CDK1 levels ↓ phosphorylated GSK3β ↓ β-catenin gene expression Supports normal breast cell proliferation or growth* Prevents tumour locoregional recurrence in vivo* Causes significant breast cancer cell death*	[53, 55, 56, 59–63]
	KPL-1 cell line MKL-F cell line	↑ Apoptosis ↑ Bak expression levels Activates caspase 3 ↓ Bcl-2 expression levels ↑ Bax expression levels	[53]
	MDA-MB-468 cell line	↓ Cell viability ↓ Proliferation ↑ Apoptosis Blocked Wnt/β-Catenin ssignalling ↓ Phosphorylated LRP6 ↓ Phosphorylated DVL2 ↓ phosphorylated GSK3β ↓ β-catenin gene expression	[60]
	MDA-MB-231 xenografts MMTV-Wnt1 transgenic mice	↓ Tumour progression ↓ Ser9 phosphorylated GSK3β ↓ Wnt/β-Catenin ssignalling ↓ CDK levels ↓ Phosphorylated LRP6 ↓ Phosphorylated and unphosphorylated DVL2 ↓ Active β-catenin
Haematopoietic	Acute human T cell leukaemia cells (Jurkat clone E6-1) NSO myeloma cells HL-60 human promyelocytic leukaemia cells Human Burkitt lymphoma cells (Ramos)	↓ Number of viable cells ↑ Apoptosis Acts in absence of p53 ↓ Vacuolar ATPase No significant toxicity, apoptosis, or decrease in normal cells	[64]
	Acute human T cell leukaemia cells (Jurkat clone E6-1)	↑ Phosphorylation of p38-MAPK	[65]
	Wt-p53Molt-4 cells (T-ALL)	↓ Survivin protein levels ↑ Caspase 3 levels ↑ accumulation of P53 Less uniform cells without membrane integrity ↓ Number of viable cells Diminishes metabolic activity ↓ Rate of proliferation	[66]
	CCRF-CEM cells	↓ Proliferation rate ↓ Viable cell number ↓ Survivin mRNA and protein levels ↓ MMP-9 mRNA and protein levels ↑ Caspase 3 ↑ Apoptosis	[67]
	B and T cells	↑ Apoptosis ↑ Caspase 3 levels ↑ Caspase 9 levels	[68]
HCC	HepG2 WiDr cells	Changes cellular morphology to apoptotic types Disrupts cell connections ↓ Cell proliferation ↓ Metabolic activity Activates caspase 3 ↓ survivin expression ↑ Apoptotic rate ↑ Anticancer activity	[48, 69]
Pancreatic	H8898 cell line	↓ Cell proliferation ↑ mitotic arrest ↑ ROS levels Cell death DNA fragmentation ↑ Apoptosis	[70]
Lung	Doxorubicin-sensitive A549 cell line Doxorubicin-resistant anti-Dox-A549 cell line	↑ Cytotoxicity ↑ Anticancer activity ↑ PARP cleavage ↑ Apoptosis Activates autophagy ↓ Autophagic inhibitor expression Activates non-PI3K-Class III/Beclin-1 inducer expression ↓ PI3K-p85/AKT/mTOR signalling pathways	[48, 71, 72]
	Doxorubicin-sensitive- and -resistant-bearing C57BL/6 mice	No acute toxicity ↓ Tumor cell accumulation around the trachea
	A549 cell line HSAEC cells (i.e., an immortalised healthy cell line)	No cytotoxic effect on healthy cells ↓ Cell viability Changes morphology ↓ DNA replication ↑ Metabolic rewiring	[72]
	A549 cells CL1-5 cells H23 cells 293 T cells	↑ p27KIP1 expression Stabilises p27KIP1 through transcriptional repression of SKP2 ↓ E2F1 ↓ PKB levels	[73]
	95-D cells	↓ RhoA gene expression and protein levels ↓ MMP-2 ↓ Metastasis and invasion ↑ Cell aggregation	[74]
	GLC cell line	↑ Mitochondrial apoptosis via caspase-dependent and independent manner ↑ Cytochrome c and AIF release into the cytoplasm	[75]
	GLC4/ADR cell line	↑ Cytochrome c release Activates caspase cascade ↑ PARP cleavage	[76]
Urothelial	CNE2 cells	↓ Cell proliferation ↓ Cell migration ↓ Cell invasion Interrupts the cell cycle in G0/G1 phase	[77]
Nasopharyngeal	Cisplatin-sensitive or resistant cells  J82  253 J  T24  RT-112	Blocked autophagy Resensitised cisplatin-resistant cells to apoptotic cell death In combination with cisplatin, prodigiosin sensitised both cisplatin-sensitive and -resistant cell lines to cisplatin ↓ Activities of cathepsin B and L Alters lysosomal function	[22]
Choriocarcinoma	JEG3 cell line	↓ IAP family, including XIAP, cIAP-1 and cIAP-2 ↓ Cell growth ↑ Apoptosis ↑ Caspase 3 levels ↑ Caspase 9 levels ↑ PARP cleavage ↑ P53 expression level ↑ Bax/Bcl-2 expression level	[78, 79]
Prostate cancer	PC3 cell line PC3 and JEG3 tumour-bearing nude mice	↓ Cell and tumour growth ↑ Bax/Bcl-2 expression level ↑ Apoptosis ↑ PARP cleavage ↑ Caspase 3 levels ↑ Caspase 9 levels ↑ P53 expression level ↓ IAP family, including XIAP, cIAP-1 and cIAP-2	[78]
Melanoma	The substrain B16BL6 of mouse melanoma B16 cells	↓ Metastasis and invasion ↑ Mouse survival rate	[74]
	SK-MEL-5 cell line	Activates the mitochondrial apoptotic pathway Disrupts MCL-1/BAK complexes ↓ mTORC1 protein levels ↓ mTORC2 protein levels Loss of AKT phosphorylation	[80, 81]
	SK-MEL-28 cell line	Cell cycle arrest at G0/G1 phase ↑ Apoptosis ↑ DNA damage ↓ Survivin protein levels ↓ Clonogenic capacity in survivin knockdown cells ↓ mTORC1 protein levels ↓ mTORC2 protein levels Loss of AKT phosphorylation	[81, 82]
	SK-Mel-19 cell line	Cell cycle arrest at G0/G1 phase ↑ Apoptosis ↑ DNA damage ↓ Survivin protein levels ↓ Clonogenic capacity in survivin knockdown cells	[82]

↑denotes overexpression, upregulation, overactivation, or induction, whereas ↓ expresses reduced activity, suppression, or downregulation

^*According to the in-vitro and in-vivo results of an experimental study of prodigiosin-encapsulated scaffolds using blended FDA-approved polymers (polylactic-co-glycolic acid [PLGA], polyethylene glycol [PEG] and polycaprolactone [PCL])

5-FU, 5-fluorouracil; ADR, adriamycin-resistant; AIF, apoptosis-inducing factor; ALL, acute lymphocytic leukaemia; ATP, adenosine triphosphate; ATPase, adenosine triphosphatase; Bax, Bcl-2-associated X protein; Bad, Bcl-2-associated death promoter; Bcl-2, B-cell lymphoma-2; Bak, Bcl2 antagonist/killer; B-CLL, B-Cell chronic lymphocytic leukaemia; BCRP, breast cancer resistance protein; BiP/GRP78, binding immunoglobulin protein-glucose-regulated protein 78; CDK1, cyclin dependent kinase 1; CHOP, C/EBP homologous protein; cIAP-1, cellular inhibitor of apoptosis protein-1; cIAP-2, cellular inhibitor of apoptosis protein-2; CRC, colorectal cancer; CRCSCs, colorectal cancer stem cells; DVL2, dishevelled segment polarity protein 2; E2F1, E2F transcription factor 1; EGFP-LC3, enhanced green fluorescent protein-microtubule-associated protein 1A/1B-light chain 3; EGFR, epidermal growth factor receptor; ER, endoplasmic reticulum; ETC, electron transport chain; GRP78, glucose-regulated protein 78; GSK3β, glycogen synthase kinase 3 beta; HSAEC, human primary small airway epithelial cells; HSP90ɑ, heat shock protein 90 alpha; IAP, inhibitor of apoptosis protein; IRE1–JNK, inositol requiring enzyme 1-c-Jun NH2-terminal kinase; LRP6, low-density lipoprotein receptor-related protein 6; MAPK, mitogen-activated protein kinase; MCL-1/BAK, myeloid-cell leukaemia 1-Bcl2 antagonist/killer MDCK, madindarby canine kidney; MDR1, multidrug resistance 1; MKL, megakaryoblastic leukaemia 1; MMP-2, matrix metalloproteinase-2; MMP-9, matrix metalloproteinase-9; MRP, multidrug resistance-associated protein; MMTV-Wnt1, mice transgenic for mouse mammary tumour virus-Wnt1; mTOR, mammalian target of rapamycin; NAG-1, nonsteroidal anti-inflammatory drug-activated gene-1; PARP, poly (ADP-ribose) polymerase; PERK–eIF2α, protein kinase R (PKR)-like endoplasmic reticulum kinase-eukaryotic translation initiation factor 2A; PI3K, phosphoinositide 3-kinase; PKB, protein kinase B; PUMA, P53 upregulated modulator of apoptosis; ROS, reactive oxygen species; SCLC, small cell lung cancer; SKP2, S-phase kinase associated protein 2; SQSTM, sequestosome; sXBP1, spliced X-box binding protein 1; VEGF, vascular endothelial growth factor; XIAP, X-linked inhibitor of apoptosis