Table 1.

Different PNE and their anticancer mechanisms

P. nigrum plant part used	Sample used	Phytochemical/Compounds identified	Experimental model	IC50/Doses	Anticancer activity	Refs.
Dried fruit	Piperine-free P. nigrum fruits extract (PFPE)	n.d.	In vitro: Breast cancer cells MCF-7 ZR-75-1 In vivo: NMU-treated female Sprague–Dawley mammary tumor rats	MCF-7 (IC50 = 7.45 µg/mL), ZR-75-1 (IC50 = 7.45 µg/mL) (Dose = 100, 200, 400 mg/kg BW)	Showed cancer prevention effects through ROS generation in vivo ↓ MMP-2, ↓MMP-9, ↓VEGF in vivo ↓ cancer cells proliferation activity by downregulated trancription factor, c-Myc in vitro	[26]
Dried fruits of black peppercorn	Low piperine fractional P. nigrum extract (PFPE)	Fifteen compounds were detected, and caryophyllene is a majority with 25%	In vivo: NMU-Induced Sprague–Dawley mammary tumor rats	(Dose = 200 mg/kg BW)	↓ tumor progression ↑ the antitumor immunity by regulating the Th1/Th2/Treg	[27]
Dried fruits	Ethanolic extract rich in piperamides	Two major compounds of piperamides: piperine and piperyline	In vitro: MCF-7 cells human breast cancer HT-29 human colorectal adenocarcinoma In vivo: Ehrlich ascites carcinoma-bearing mice	MCF-7 human breast cancer cells (IC50 = 27.1 µg/mL), HT-29 colorectal adenocarcinoma (IC50 = 80.5 µg/mL) (Dose = 100 mg/kg BW)	↓ cell proliferation in MCF-7 and HT-29 cells ↓ Tumor growth in vivo ↑ oxidative stress and apoptosis in vitro and in vivo ↑ Bax, ↑p53, Bcl-xL expression associated with apoptosis Tumor cell death related to oxidative stress in MCF-7	[28]
Dried fruits	Aqueous water	P. nigrum tin oxide nanoparticle (SnO2 NPs)	In vitro: human breast cancer cell MCF-7 In silico: EGFR receptor	Dose = 75–200 µg/mL	The favorable pharmacokinetics pharmacodynamics, and toxicity profiles of three promising compounds in silico Exhibited cytotoxicity against cancer cell in vitro	[29]
Dried unripe fruits of black pepper	Ethanolic extract	Phenolic group	In vitro: Human colorectal cancer cells line HCT-116 HCT-15 HT-29	HCT-116: IC50 = 4.0 µg/mL, HCT-15: IC50 = 3.2 µg/mL, HT-29: IC50 = 7.9 µg/mL	Inhibited cell proliferation	[33]
Dried fruits	Methanol extract or dichloromethane extract	Alkaloids group	In vitro: Human Breast cancer cells MCF-7 MDA-MB-231 MDA-MB-468	MCF-7: IC50 = 20.25 µg/mL, MDA-MB-231: IC50 = 22.37 µg/mL, MDA-MB-468: IC50 = 9.04 µg/mL	Inhibited cell proliferation	[34]
Unripe fruit	Ethanolic extract	Alkaloids gropus including piperine as a major constituent	In vitro: PANC-1 human pancreatic cancer	IC50 = 54.2 µg/mL	Inhibited proliferation of PANC-1 through G0/G1 arrest ↓ protein levels of cell cycle regulators such as cyclin B1, cyclin D1, survivin, and Forkhead box M1 (FoxM1) ↓ cell migration and invation by decreasing FoxM1 protein level	[35]
Black pepper	Piperine enriched supercritical extract	Piperine is major compound was identified	In vitro: MCF-7 human breast cancer cells In vivo: Balb/c mice-bearing Ehrlich Ascites Carcinoma (EAC) In silico: piperine binding to CDK2-Cyclin A and BCl-xL	IC50 = 27.8 µg/mL Dose = 100 mg/kg BW	↓ growth of breast cancer cell line MCF-7 that confirmed by interaction of piperine and protein targets CDK2-Cyclin A and BCl-xL ↑ apoptosis in MCF-7 breast cancer cells Inhibited tumor growth and showed lower levels of CDK2 and Cyclin A ↑ cell cycle arrest in G2/M phase in vivo ↑apoptotic cells and upregulated of pro apoptotic proteins (p53 and Bax) Hydrophobic interactions between piperine and residue Ser5 in CDK2; with residue Lys8 in Cyclin A; and Bcl-xL receptor	[36]
Dried young fruit	Ethanolic extract	n.d.	In vitro: Human breast cancer cells MCF‑7	IC50 = 15.6 μg/mL	Stimulated growth inhibition by increasing the G1 phase arrest and inhibiting cyclin D1 and NF‑κB Inhibited cell migration and reduced MMP-2, MMP 9, VEGFA, and ICAMP1 genes level Activated the ROS formation, increase caspase‑3 activity, and induced breast cancer cell death	[30]
Dried young fruit	Ethanolic extract	Phenolic and flavonoid contents including Piperine	In vitro: HeLa human cervical cancer cells	IC50 = 22.71 µg/mL	Inhibited cell ploriferation and induced cell cycle arrest at G0/G1 phase Triggered apoptosis by inhibiting mitochondrial function and amplifying ROS production Suppressed cancer cells migration	[31]
Dried young fruit	Ethanolic extract	n.d.	In vitro: Cholangiocarcinoma (CCA) /bile duct cancer KKU‑100 KKU‑M452	KKU-100 IC50 = 12.76 µg/mL, KKU-M452 IC50 = 38.32 µg/mL	Inhibited cell viability and colony formation Decreased cell growth by cell cycle arrest at G0/G1 phase in KKU‑100 cells and S to G2/M phase in KKU‑M452 cells Induced apoptosis by decreasing mitochondrial function and increasing ROS production Suppressed cell migration	[37]
Black pepper seed	Aqueous extract	PNE silver nanoparticles (AgNPs): nineteen phytochemicals such as piperine, piperanine, ecuramide, pipecolic acid, betaine, salsolinol, hexadecanamide, oleamide, quinine	In vitro: MDA-MB-231 human breast cancer PANC-1 human pancreatic cancer SKOV-3 human ovarian cancer PC-3 human prostate cancer HeLa human servical cancer	MDA-MB-231: IC50 = 10 µg/mL PANC-1: IC50 = 10 µg/mL, SKOV-3: IC50 = 10 µg/mL PC-3: IC50 = 10 µg/mL HeLa: IC50 = 10 µg/mL	Showed potent cytotoxicity against human cancer cell lines	[32]
Black pepper seed	Aqueous extract	P. nigrum tin oxide nanoparticle (SnO2 NPs)	In vitro: HCT-116 human colorectal cancer A549 human lung cancer	HCT-116: IC50 = 0.165 µg/mL A549: IC50 = 0.135 µg/mL	Demonstrated toxicity towards HCT 116 and A549 cells through the generation of ROS	[38]
Black pepper seed	Ethanolic extract	Characterized piperine	In vitro: Human metastatic melanoma SK-MEL 19 cells Intestinal adenocarcinoma malignant ascites AGP-01 Intestinal adenocarcinoma with an inactivated PIWIL1 gene AGP-01 PIWIL1−/− Neoplastic human pulmonary fibroblast cell line MCR5	SK-MEL 19: IC50 = 14.94 µg/mL AGP-01: IC50 = 13.52 µg/mL AGP-01 PIWIL1−/− IC50 = 21.26 µg/mL MCR5: IC50 = 14.17 µg/mL	Induced cancer cells toxicity	[39]
Dried fruit	Aqueous extract	P. nigrum AgNPS	In vitro: Human hepatocyte carcinoma HepG2	IC50 = 4.98 µg/mL	Induced cancer cells toxicity	[40]
Dried fruit	Aqueous extract	P. nigrum AgNPs	In vitro: Human breast cancer cells MCF-7 Human larynx carcinoma cancer Hep-2	MCF-7: IC50 = 52 µg/mL Hep-2: IC50 = 54 µg/mL	Induced cancer cells toxicity	[41]
Dried black pepper	Aqueous extract Methanolic extract	Mainly piperine and alkyl amides	In vitro: Human colon carcinoma HCT-116 Human breast cancer MCF-7 Human glioblastoma SF-268 Human lung carcinoma NCI-H460	HCT-116, MCF-7, SF-268, NCI-H460: IC50 = 200 µg/mL	Induced cancer cells toxicity	[42]
Dried fruit	CHCl3 extract	Alkaloids group (piperidine present)	In vitro: Human servical cancer HeLa	IC50 = 17.47 µg/mL	Induced cancer cells toxicity	[43]
Dried fruit	Extract of methanol:water 1:1	n.d.	In vivo: DMBA-induced skin tumorigenesis in Swiss albino mice	Dose = 150 mg/kg BW	Reduced the number of tumours in vivo test model	[44]
Dried fruit	Ethanolic extract	n.d.	In vitro: Murine Ehrlich Ascites Carcinoma EAC Murine melanoma-B16 Human servical cancer HeLa	Murine Ehrlich Ascites Carcinoma EAC: IC50 = 8 µg/mL, Murine melanoma-B16: IC50 = 10 µg/mL, HeLa: IC50 = 17 µg/mL	Induced cancer cells toxicity	[45]
Dried fruit	n-hexane, chloroform, methanol and water extracts	Phenolic content	In vitro: Human cervical cancer cell line CaSki	IC50 = 36 µg/mL	Induced cancer cells toxicity	[46]
Dried black pepper	Dichloromethane extract	Piperine free P. nigrum extract (PFPE), rich in pipercitine alkaloid and caryophyllene terpene	In vitro: Human cholangiocarcinoma KKU-100 KKU-M213 KKU-M055	KKU 100: IC50 = 17.79 µg/mL, KKU M213: IC50 = 13.70 µg/mL, KKU M055: IC50 = 16.74 µg/mL	Induced cancer cells toxicity	[47]
Dried leaves	Methanolic extract	Major: Tannin, flavonoid, steroid, polyphenol Minor: saponin, terpenoid, triterpenoid, alkaloid	Human lung carcinoma A549	Dose = 200–500 µg/mL	Induced cancer cells toxicity	[48]
Dried root	Extracts: petroleum ether and CHCl3 petroleum ether CHCl3	Alkaloids group	In vitro: Human leukemia cells HL 60	Petroleum ether: IC50 = 30 µg/mL, CHCl3: IC50 = 11.2 µg/mL, Combined: IC50 = 9.8 µg/mL	Induced cancer cells toxicity	[49]
Black pepper	Supercritical carbon dioxide extracts rich in piperine (SFE)	Piperine is major compound was identified	In vivo: Balb/c mice bearing-Ehrlich ascites carcinoma cells (EAC) In silico: dGlutathione Peroxidase	Dose = 100 mg/kg BW	Inhibited EAC cells viability Enhanced EAC pro-oxidative status to induced oxidative stress Decreased glutatione peroxidase/GPx activity and GSH depletion The GPx-piperine poses hydrogen and hydrophobic bonds that contribute to inhibitionof GPx	[50]
	n.d	Five lead compounds: Clarkinol A Isodihydrofutoquinol B Burchellin Kadsurin B Lancifolin C	In silico: Five lead compounds to Epidermal growth factor receptor (EGFR)	Binding score: − 7.304 to − 6.342 kcal/mol	Interacted well with EGFR receptor	[51]
	n.d	Campesterol Cholesterol Piperine Linoleic acid	In silico: PPARγ, a glucose metabolism regulator factor that responsible for colorectal cancer	Binding score: Campesterol (− 8.8 kcal/mol), Cholesterol (− 8.2 kcal/mol), Piperine (− 8.6 kcal/mol), Linoleic acid (− 6.2 kcal/mol)	Interacted well with PPARγ target	[52]
	Pure Piperine (97–98%) dissolved in DMSO	Piperine	HT-29 colon carcinoma cells	IC50 = 75–150 μM	Inhibited HT-29 colon carcinoma cell proliferation by inducing G1 phase cell cycle arrest Triggered apoptosis by producing hydroxyl radical	[53]
Dried roots	P. nigrum in petroleum ether and chloroform extracts	Several alkaloid groups such as: pellitorine, (E)-1-[30,40-(methylenedioxy) cinnamoyl] piperidine, 2,4-tetradecadienoic acid isobutyl amide, piperine, sylvamide, cepharadione A, piperolactam D and paprazine	HL60 (human promyelocytic leukaemia cells)	IC50 = 30 µg/mL	Inhibitory effect toward HL60 (human promyelocytic leukaemia cells)	[49]

IC₅₀: half-maximal inhibitory concentration; BW: body weight; PNE: P. nigrum extract; AgNPs: silver nanoparticles; PFPE: Piperine-free P.nigrum extract; PFPE-CH: Piperine-free P. nigrum extract combined with coconut oil and honey ROS; Reactive Oxygen Species: NMU: N-nitroso-N-methylurea; DMBA: 7:12-dimethylbenz[a]anthracene; n.d: not determined