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)
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
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)
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
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
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
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
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
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
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
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
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
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
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
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
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.