Inducers of Senescence, Toxic Compounds, and Senolytics: The Multiple Faces of Nrf2-Activating Phytochemicals in Cancer Adjuvant Therapy

Table 2

Clinical trials of adjuvant (or alternative) therapies with natural bioactive compounds in cancer.

n	Compound	Dose	Drug	Patients and scheme	Results of the trial	Ref.	Established link with the drug and induction of cellular senescence
1	Tocotrienols	200 mg twice per day of tocotrienol-rich fraction	Tamoxifen	Double-blinded placebo-controlled trial in 240 women with early breast cancer subdivided in 2 groups: tocotrienol-rich fraction (TRF) plus tamoxifen and placebo plus tamoxifen	No association between adjuvant tocotrienol therapy and breast cancer-specific survival (risk of mortality due to breast cancer was 60% lower in tocotrienol group but not statistically significant)	[81]	[290]
2	Curcumin	Tablets containing 500 mg Meriva, a proprietary lecithin delivery system containing 100 mg curcuminoids (33 parts of curcumin, 8 parts of demethoxycurcumin and 1 part of bis-demethoxycurcumin)	Patients were under different chemotherapy or radiotherapy regimen	A controlled study on the possibility to alleviate adverse effects of cancer treatment with Meriva. Half of patients () received Meriva plus the “best available treatment” and the other half (, control groups) received only the “best available treatment”	Results showed that lecithinized curcumin might alleviate the burden of side effects associated to chemo- and radiotherapy	[97]	—
2	Curcumin	2.0 grams of curcumin or placebo orally three times per day (i.e., 6.0 grams daily)	Radiotherapy	Randomized, double-blind, placebo-controlled clinical trial to assess the ability of curcumin to reduce radiation dermatitis severity in 30 breast cancer patients	Curcumin significantly reduced the severity of radiation dermatitis (fewer moist desquamation)	[291]	[292]
2	Curcumin	Oral administration of highly bioavailable curcumin (Theracurmin) containing 200 mg or 400 mg of curcumin	Gemcitabine-based chemotherapy	A phase I clinical study on 16 pancreatic or biliary tract cancer patients who failed standard chemotherapy	No unexpected adverse events were observed and 3 patients safely continued Theracurmin administration for >9 months	[293]	[294]
2	Curcumin	360 mg curcumin three times daily presurgery (10–30 days)	Radiotherapy, chemotherapy, chemoradiotherapy, or no additional therapy	A placebo-controlled clinical trial randomized 126 patients with colorectal cancer to either receive curcumin or placebo	Curcumin administration increased body weight, decreased serum TNF-alpha levels, increased apoptotic tumor cells, enhanced expression of p53 molecule in tumor tissue, and modulated tumor cell apoptotic pathway	[95]	—
2	Curcumin	Oral curcumin 8 g/day	Gemcitabine-based chemotherapy	A preliminary study in 17 patients with advanced pancreatic cancer	5 patients (29%) discontinued curcumin within few weeks due to abdominal fullness or pain (observed in 7 patients), and the dose of curcumin was reduced to 4000 mg/day. One of 11 evaluable patients (9%) had partial response, 4 (36%) had stable disease, and 6 (55%) had tumor progression	[295]	[294]
2	Curcumin	Oral curcumin 8 g/day	Gemcitabine-based chemotherapy	A phase I study in 21 gemcitabine-resistant patients with pancreatic cancer	No patients were withdrawn from this study because of the intolerability of curcumin	[96]	[294]
2	Curcumin	Curcumin was orally given from 500 mg/d for seven consecutive d by cycle (from d-4 to d + 2) and escalated until a dose-limiting toxicity should occur	Docetaxel chemotherapy	An open-label phase I trial in 14 patients with advanced and metastatic breast cancer	Maximal-tolerated dose of curcumin was established to 8000 mg/d. Some improvements as biological and clinical responses were observed in most patients	[296]	[297]
2	Curcumin	Patients received 8 g curcumin by mouth daily until disease progression, with restaging every 2 months	Individuals who underwent radiotherapy or chemotherapy <4 weeks beforehand were excluded from the study	A nonrandomized, open-label, phase II trial of curcumin in 25 patients with histologically confirmed adenocarcinoma of the pancreas	One patient had ongoing stable disease for >18 months and another had a brief, but marked tumor regression (73%) accompanied by significant increases (4-fold to 35-fold) in serum cytokine levels (IL-6, IL-8, IL-10, and IL-1 receptor antagonists). No toxicities were observed	[298]	—
2	Curcumin	Curcuma extract in proprietary capsule form was given at doses between 440 and 2200 mg/day, containing 36–180 mg of curcumin	Patients received various previous chemotherapy or radiotherapy	A preliminary study in 15 patients with advanced colorectal cancer refractory to standard chemotherapies	Curcuma extract was administered safely to patients at doses of up to 2.2 g daily, equivalent to 180 mg of curcumin but a low bioavailability of curcumin in humans was also observed	[299]	—
3	EGCG	Dose escalation proceeded according to a standard phase I design from 40 μM to 440 μM	Cisplatin and etoposide	Single-arm phase I study in 24 patients with unresectable stage III non-small-cell lung cancer	Dramatic regression of esophagitis was observed in 22 of 24 patients and mean pain score was reduced	[114]	[300, 301]
3	EGCG	Double-brewed green tea at 500 ml day	Platinum/taxane	Maintenance treatment after chemotherapy in 16 women with advanced stage ovarian cancer	Only 5 of 16 women remained free of recurrence after 18 months	[302]	[303]
3	EGCG	2000 mg twice a day	—	Single-arm phase II trial in 42 patients with asymptomatic, Rai stage 0 to II chronic lymphocytic leukemia who did not meet criteria to initiate conventional chemotherapy treatment	29 patients (69%) showed decline ≥ 20% in the lymphocyte count and/or a reduction ≥ 30% in the sum of the products of all lymph node areas during the 6 months of treatment	[304]	—
3	EGCG	Green tea extract 375 mg per day	—	Single-arm study in 19 hormone-refractory prostate cancer patients	No patient had a prostate-specific antigen response (i.e., at least 50% decrease from baseline), and all 19 patients were deemed to have progressive disease within 1 to 5 months	[305]	—
3	EGCG	6 g of powdered green tea extract daily	—	Phase II trial of green tea in the treatment of 42 patients with androgen-independent metastatic prostate carcinoma	Limited antineoplastic activity, as defined by a decline in PSA levels (decline > 50% in the baseline PSA value, occurred in a single patient) and 4 episodes of toxicity, was observed	[306]	—
4	Quercetin	Quercetin 20 mg orally 3 times a day in combination with curcumin (480 mg)	—	A phase I trial in patients with familial adenomatous polyposis with prior colectomy	All 5 patients had a decreased polyp number and size from baseline after a mean of 6 months of treatment with curcumin and quercetin	[307]	—
4	Quercetin	Short i.v. infusion at escalating doses from (1400 mg/m2 was recommended)	Previous chemotherapy was reported for 40/51 patients	A phase I and phase II trial in patients with various cancer no longer amenable to standard therapies	In 9 of 11 patients, lymphocyte protein tyrosine phosphorylation was inhibited. In one patient with ovarian cancer and in another patient with hepatoma, circulating tumor markers were decreased	[132]
5	Genistein	In escalating doses (400 mg–1600 mg daily) of a multicomponent crystalline form	Concomitant gemcitabine treatment (1000 mg/m^2)	A phase I study in 16 patients with inoperable pancreatic carcinoma	No signs of toxicity observed. The median overall survival time was 4.9 months (range 1.5–19.5 months)	[308]	—
5	Genistein	30 mg genistein or placebo capsules daily for 3–6 weeks before radical prostatectomy	—	A phase II placebo-controlled, randomized, double-blind clinical trial was conducted in 47 patients with prostate cancer	No significant effects on proliferation-, cell cycle-, apoptosis- or neuroendocrine biomarkers. Modulation of the expression of some biomarkers related to prediction and progression	([309]; [310])
5	Genistein	Oral genistein (300 or 600 mg/d as the purified soy extract G-2535) for 14 to 21 days before surgery	—	A phase II randomized, placebo-controlled trial in 59 subjects diagnosed with urothelial bladder cancer	Reduction in bladder cancer tissue p-EGFR staining at dose of 300 mg. No other significant differences in the multitude of clinical molecular parameters measured
6	Resveratrol	Micronized resveratrol at 5 g daily	Bortezomid	A phase II study of SRT501 (resveratrol) with bortezomib in 24 patients with relapsed and or refractory multiple myeloma	Unacceptable safety profile and minimal efficacy in patients with relapsed/refractory multiple myeloma	[170]	[311]
6	Resveratrol	Micronized resveratrol at 5 g daily	—	Phase I randomized, double-blind pilot in patients with colorectal cancer and hepatic metastases	Administration was safe. A small but significant increase in cleaved caspase-3 immunoreactivity in tumor tissue compared to placebo was detected	[171]	—
7	Silybin	Dose escalation from 2 to 12 g per day with silybin-phosphatidylcholine	—	Phase I dose-preliminary study in 3 patients with advanced hepatocellular carcinoma not eligible for other therapies	All patients died soon after enrolment and were not possible to conclude about the effects	[182]	—
7	Silybin	Dose escalation from 2.5 to 20 g per day with silybin-phytosome	—	Phase I pharmacokinetic study in 13 patients (over 70 years) with prostate cancer	No response on prostate-specific antigen was observed and one patient displayed grade 3 toxicity	[312]	—
8	PEITC	10 mg in 1 ml of olive oil, 4 times per day, for 1 week	—	Not an adjuvant therapy, but a clinical trial with a crossover design versus placebo in 18 smokers	Metabolic activation of one carcinogen was reduced by treatment	[192]
9	Sulforaphane	200 μmoles/day of sulforaphane-rich extracts for a maximum period of 20 weeks	—	Phase II study in 20 patients with recurrent prostate cancer	Treatment did not lead to ≥50% PSA declines in the majority of patients. A significant lengthening of the on-treatment PSA doubling time was observed compared with the pretreatment PSA doubling time. Administration was safe with no grade 3 adverse events	[208]	—
10	Triptolide	2 weekly infusions for 3 weeks with 2 mg of a semisynthetic derivate of triptolide, which is converted to triptolide in vivo (F60008)		Phase I trial in 20 patients with advanced solid malignancy for whom standard therapy options did not exist	Treatment-induced mild grade 1-2 anaemia, fatigue, nausea, vomiting, diarrhea, and constipation. Two lethal events were observed	[219]
11	Allicin	Local application of allicin, via gastroscopy (48 h before surgical intervention)	—	Trial on 40 patients with progressive gastric carcinoma versus 40 controls	In cancer tissues removed by surgery, cell apoptosis rate was 9.60 versus 2.20 in the control group. There were additional differences in the expression of proapoptotic genes and in cell cycle progression	[313]
12	Berberine	20 mg kg− 1 once a day	Radiation therapy	Two arm study in 90 patients with non-small-cell lung cancer. The trial group received radiation therapy plus berberine, and the control group received radiation therapy plus a placebo for 6 weeks	Reduced the incidence of radiation-induced lung injury and improved pulmonary function	[243]	[292]
13	Piperlongumine	No clinical trial	—	—	—	—	—
14	Fisetin	No clinical trial	—	—	—	—	—
15	Phloretin	No clinical trial	—	—	—	—	—

When the natural bioactive compound was used as adjuvant therapy, otherwise not applicable. Explicative references that identify mechanisms related to senescence induction of the chemotherapy drugs or treatments reported in the adjuvant therapy.