Table 1.

Phytochemicals are associated with ROS-mediated programmed cell death in cancer.

Sr. No.	Phytochemical	PCD Type	Effective Anti-Cancer Concentration (In Vitro)	Dose Administered (In Vivo)	Pharmacokinetic Data	TttCell Lines/Subjects	Outcome/Comments	References
1	Capsaicin	Apoptosis	150 µM	2.5 mg/kg	Not stated	Animal subject—Mice In vitro study Pancreatic cancer cells	Apoptosis was observed in AsPC-1 and BXPC3 cell lines at 150 µM concentration, while no effect were observed in normal (HPDE-6) cells. In an animal study, an oral dose 2.5 mg/kg was effective in suppressing tumor growth. Human equivalent dose—0.202 mg/kg.	[67,68]
2	Capsaicin (Pharmacokinetic study)	-	-	5 g	Cmax: 2.47 ± 0.13 ng/mL	Human subjects	The oral bioavailability of capsaicin is effective for anti-diabetic effect, but plasma level is less for its anti-cancer activity.	[123,124]
3	Sulforaphane	Apoptosis	5–10 µM	-	-	-	Various studies report anticancer activity in a range of 5–10 µM which is not attainable through dietary intake. A study in normal vs. cancerous prostate cells revealed selective cytotoxicity of sulforaphane in cancerous cells. No effect was observed in normal cells at a dose range of 0–15 µM.	[125,126]
4	Sulforaphane (Pharmacokinetic study)	-	-	30 mg/kg	Cmax: 772.8 ± 54.36 ng/mL	Animal subject—Rats	Nano structured lipid formulation of sulforaphane increased its bioavailability in rat plasma wherein a dose close to effective anticancer level was achieved.	[127]
5	α-lipoic acid	Apoptosis	500 µM	-	-	In vitro study hepatoma cell line	ROS-mediated apoptosis was observed at 500 µM. However, in another study, no effect was observed in normal L02 liver cells at 5 mM concentration.	[72,128]
6	α-lipoic acid (Pharmacokinetic study)	-	-	600 mg per day	Cmax: 8–52 nM	Human subjects	Plasma levels achieved in plasma following oral administration of racemic α-lipoic acid is much less than required for its anti-cancer activity.	[129]
7	BITC	Apoptosis	-	-	-	In vitro study Pancreatic cancer cells	BITC caused ROS generation in a concentration dependent manner starting from 2.5 to 20 µM in MIAPaCa-2 and Capan-2 cell lines	[79,130]
8	BITC	Apoptosis	<2.5–5 µM	-	-	In vitro study Breast cancer cells and normal mammary epithelial cell line	BITC induced ROS-mediated apoptosis in MDA-MB-231 and MCF-7 at IC50 value of <2.5 µm and 5 µM respectively at 24-h time point. However, the IC50 was 20 µM in normal mammary epithelial cell line MCF-10A.	[131]
9	BITC	Apoptosis	8 µM	-	-	In vitro study Pancreatic cancer cells	An IC50 of 8 µM was observed when BXPC3 cells were treated with BITC.	[132]
10	BITC (Pharmacokinetic study)	-	-	12 µM/day	Cmax: 7.5 µM in tumor	Animal subject—Mice	BXPC3 cells were subcutaneously implanted and a 43% tumor inhibition was observed with a concentration near IC50 value achieved in plasma.	[74]
11	PEITC	Apoptosis	<5 µM	-	-	In vitro study Breast cancer cells	PEITC caused ROS-mediated apoptosis in MDA-MB-231 and MCF-7 cell lines.	[86]
12	PEITC	Apoptosis	5–10 µM	-	-	In vitro study normal ovarian epithelial cell line	Ovarian epithelial cell line T72 was transfected to over express Ras oncogene to form oncogenic T72Ras cell line. Following PEITC treatment, the transformed cells showed higher sensitivity to ROS as compared to normal cells. Thus, showing selective activity of PEITC.	[133]
13	PEITC (Pharmacokinetic study)	-	-	10–100 µmol/kg	Cmax: 9–42 µM	Animal subjects—Rats	A considerably high level of PEITC was achieved after oral administration of PEITC than required for its anti-cancer activity.	[134]
14	Piperine	Apoptosis	136–137 µM	-	-	In vitro study Melanoma cell lines	Piperine induced RPS mediated apoptosis in SKMEL-28 and B16-F0 cells at 136 µM and 137 µM respectively at 72-h time point.	[90]
15	Piperine	Apoptosis	132 µg/mL	-	-	In vitro study Lung cancer cells and normal lung fibroblasts	Piperine induced apoptotic cell death via p53 dependent mitochondrial pathway in A549 cancer cell line while no significant cytotoxicity was observed in normal WI38 human lung fibroblasts. ROS are considered to be downstream effectors of p53 mediated apoptosis.	[135,136]
16	Piperine (Pharmacokinetic study)	-	-	200 mg tablets (Benjakul formulation)	Cmax: 1.078 µg/mL	Human subjects	Piperine is a major component of a traditional Thai medication called Benjakul. A dose of 200mg resulted in a Cmax level of 1.078 µg/mL which is significantly lower than that required for anticancer effect.	[137]
17	Curcumin	Apoptosis	25 µM	5 mg/kg	-	In vitro study Colorectal cancer cells Animal subjects—Mice	Curcumin induced ROS-mediated apoptotic cell death in HCT-116 cell line at 25 µM concentration within 48hh. Curcumin showed considerable tumor inhibition in in vivo xenograft model following administration of 5 mg/kg I.P dose.	[93]
18	Curcumin	Apoptosis	20 µM	-	-	In vitro study Cervical cancer cells and normal cervical cells	Curcumin induced ROS-mediated apoptosis in cervical cancer cell lines C33A, CaSki, HeLa, and ME180 cells at approximately 20 µM in 48-h time period, while it did not induce significant toxicity in normal counterparts until 40 µM concentration.	[138]
19	Curcumin (Pharmacokinetic study)	-	-	Various doses (2–10 g)	Cmax: 1–3200 ng/mL	Healthy human volunteers and patients (cancer, Alzheimer’s disease etc.)	The serum levels of curcumin achieved by oral administration of crude curcumin are much lower than required for anti-cancer activity. However, a 10–15-fold increase in plasma levels was observed when curcumin was formulated as nanoparticle or combined with piperine, lecithin, etc.	[139]
20	Withaferin A	Ferroptosis	5–10 µM	4 mg/kg	Not stated	In vitro study Neuroblastoma cell lines Animal subjects— Mice	Crude Withaferin A and its nano particle formulation for tumor targeting showed ROS-mediated ferroptosis at 10 µM in neuroblastoma cell lines IMR-32, SK-N-SH, Kelly, NB69, and CHP-134 within 4–8 h. Tumor regression was mediated through lipid peroxidation.	[95]
21	Withaferin A	Apoptotic	1–50 µM	4 mg/kg	Cmax: 1.8 µM	In vitro study Breast cancer cell lines Animal subject—Mice	Withaferin A displayed cytotoxicity in breast carcinoma cell lines MDA-MB 231, H1299, T47D, MCF-7, LN686, as well as normal fibroblast cell line COS-7 in a wide range of 1–50 µM at 72-h time point. The IC50 was lesser than normal fibroblasts in majority of the cancer cell lines.	[140]
22	Bromelain	Ferroptosis	-	3 mg/kg	Not stated	In vitro study Colon carcinoma cell lines and normal colon cell line. Animal subjects—Mice	Bromelain inhibited proliferation of in Kras mutant colon cancer cell lines HCT-116 and DLD-1 at 50 µg/mL, while it induced significant ferroptosis in cancer cell lines at a concentration of 5 µm when combined with Erastin as compared to normal colon cells CCD1co. Bromelain increased survival rate in treatment group as compared to vehicle group.	[81]
23	Bromelain (Pharmacokinetic study)	-	-	143 mg/kg	Cmax: Very low (specific value not stated)	Human subjects	Bromelain showed very low (ng/mL) plasma levels following oral administration at 143 mg/kg body weight.	[141]
24	Ruscogenin	Ferroptosis	7.3–28.19 µM	5 or 10 mg/kg	Not stated	In vitro study Pancreatic cancer cells Animal subjects—Mice	Ruscogenin induced significant ferroptotic cell death in pancreatic cancer cell lines BxPC-3, SW1990, PANC-1, and ASPC-1 cells, as compared to normal pancreatic cell line HPDE-6-C7 wherein not IC50 was detected at 72-h time point in HPDE6-C7 cells. Additionally, it inhibited pancreatic cancer growth in vivo.	[99]
25	Ruscogenin (Pharmacokinetic study)	-	-	8 mg/kg	Cmax: 504.50 ± 63.47 ng/mL (Mean value)	Animal subjects—Rats	Following IV administration of Ruscogenin in rats, a plasma level between 2–1000 ng/mL was observed which roughly translates to 2.35 µM, a level much lower than required for anticancer effect.	[142]
26	Oridonin	Ferroptosis	26.93 µM	-	-	In vitro study Esophageal cancer cells	Oridonin induced ferroptotic cell death in esophageal cancer cell line TE1 at 27 µM within 24-h time point.	[101]
27	Oridonin	Apoptosis	2.5–10 µM	-	-	In vitro study Esophageal cancer cell lines	Oridonin induced cellular death in human esophageal cancer cell lines (KYSE70, KYSE410, and KYSE450) at 2.5–10 µM concentration, while it showed 40% cell death in normal esophageal cell line SHEE at 40 µM, a significantly higher concentration.	[143]
28	Oridonin (Pharmacokinetic study)	-	-	20 mg/kg	Cmax: 146.9 ± 10.17 ng/mL	Animal subjects—Rats	A concentration of approximately 150 ng/mL translating to 412 nM was achieved. Combination with verapamil increased the Cmax level of oridonin to 194 ± 10 ng/mL, still a lower level for anti-cancer efficacy.	[144]
29	Cucurbitacin B	Autophagy	Approximately 1 µM	-	-	In vitro study Cervical cancer cell line and breast cancer cell lines	Cucurbitacin B induced caspase independent autophagic cell death in HeLa cells at 1 µM. Additionally, it induced autophagy and increased ROS levels in MCF-7 at 200 nM. Autophagic cell death in normal counterparts was not studied.	[104]
30	Cucurbitacin B	Apoptosis	0.2 µM	-	-	In vitro study Prostate cancer cell lines	Cucurbitacin B induced cell death and ROS production in human prostate cancer cell lines LNCaP and PC-3 at 0.2 µM while no significant cell death or ROS production was observed in normal prostate cell line PrEC.	[145]
31	Cucurbitacin B (Pharmacokinetic study)	-	-	2–4 mg/kg	Cmax: 9–31 µg/L	Animal subjects—Rats	Following an oral administration of 2–4 mg/kg, a significantly low plasma level was achieved in rat plasma than required for anti-cancer activity.	[146]
32	Silibinin	Autophagy	40 µM	-	-	In vitro study Fibrosarcoma cells	Silibinin induced autophagy in human fibrosarcoma cell lines HT1080 at 40 µM within a period of 4 h. Cellular death was concluded to be an autophagy mediated apoptosis process. Effect on normal cells was not studied.	[106]
33	Silibinin (Pharmacokinetic study)	-	-	360, 720 and 1440 mg	Cmax: 0.4, 1.4 and 4 ± 5.3 µM respectively	Human Subjects—Colorectal cancer patients	Silibinin formulated capsules showed considerably high levels required to exert its anti-tumor effect.	[147]
34	Allicin	Autophagy and apoptosis	15–30 µg/mL	-	-	In vitro study Non-small cell lung cancer cell lines	Allicin induced both autophagy and apoptosis in human lung cancer cell lines A549 and NCI-H460.	[109]
35	Carnosol	Autophagy	<25 µM	-	-	In vitro study Breast cancer cell lines	Carnosol induced ROS-mediated autophagy in triple negative breast cancer cell line MDA-MB-231. Effect on normal cell counterparts was not studied.	[113]
36	Quercetin	Autophagy	200 µM	100 mg/kg	-	In vitro study Osteosarcoma cell line Animal subjects—Mice	Quercetin induced ROS-mediated autophagic cell death in human osteosarcoma cell line MG-63 and also inhibited tumor growth in mice model.	[116]
37	Berberine	Autophagy	-	-	-	In vitro study Renal carcinoma cell lines and normal kidney cell line.	Berberine induced autophagic cell death in 786-O, ACHN cell lines via its photosensitizer activity when combined with laser. Additionally, it induced cell death in normal kidney cell line HK-2 at when combined with laser. Treatment with Berberine alone failed to induce cell death >20% in cancer cells, while it induced cell death >20% in HK-2 normal cells at 40 µM within 48 h.	[118]
38	Berberine (Pharmacokinetic study)	-	-	200 mg/kg	Cmax: 25.85 ± 7.34 µg/L	Animal subject— Rats	A plasma level of 25.85 ± 7.34 µg/L equivalent to 76 µM was achieved.	[148]
39	Nobiletin	Pyroptosis	34.85–35.31 µM	-	-	In vitro study Ovarian cancer cell lines	Nobiletin induced cytotoxicity at concentration of 35 µM but no data regarding its effect on normal cell lines were shown.	[120]
40	Nobiletin	Apoptosis	40–80 µM	100 mg/kg	-	In vitro study Ovarian cancer cell lines OVCAR-3 and A2780 Animal subject— Mice	Nobiletin exhibited cytotoxicity in ovarian cancer cell lines at 40–80 µM while the IC50 for normal ovarian cell line was around 160 µM. Additionally, significant tumor growth inhibition was observed in athymic nude mice model at a dose of 100 mg/kg.	[149]
41	Nobiletin (Pharmacokinetic study)	-	-	50 mg/kg	Cmax: 1.78 µg/mL in plasma	Animal subject—Rats	The plasma level achieved after oral administration is 1.78 µg/mL which correlates to approximately 4–5 µM.	[150]
42	Emodin	Anoikis	10 µM	-	-	In vitro study Gastric cancer cell lines	Significant difference observed in RhoA expression between cancer and normal cell lines.	[61]
43	Emodin	Apoptosis	70 µM	-	-	In vitro study Cancer cell lines isolated from breast, lung, colon, and cervix carcinomas, normal human fibroblasts, and normal human keratinocytes	No effect observed on normal cell lines after 48-h treatment while cytotoxicity was observed in cancer cell lines.	[151]
44	Emodin (Pharmacokinetic study)	-	-	4.5 mg/kg	Cmax: 0.2 ± 0.1 µM	Animal subject—Rats	The concentration of free emodin achieved in rat plasma after oral administration of rhubarb extract was found to be much lower than required for its anti-cancer activity.	[152]