Table 1 Evidence-based anticancer effects of prodigiosin
From: Rise of the natural red pigment ‘prodigiosin’ as an immunomodulator in cancer
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 | |
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 | |
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 | ||
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* | ||
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 | |
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 | |
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 | |
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 | ||
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 | ||
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] |