Phytotherapy and Nutritional Supplements on Breast Cancer 用于乳腺癌治疗的植物疗法和营养补充剂

4.2.2. Vitamin C

Vitamin C, or ascorbic acid, is an essential water-soluble vitamin that acts as antioxidant and has important biological roles such as in protein metabolism, including the biosynthesis of collagen, neurotransmitters, and L-carnitine; in immune function and in absorption of iron from plant-derived foods [391]. This vitamin, which is crucial for the structural integrity of intercellular matrix, is produced by the most animals but not by humans who must get it from the diet or as supplement.

There is restricted evidence of using vitamin C supplementation in the primary prevention or delay of total cancer incidence, including breast cancer [115, 393]. One of the largest studies in women, followed up for 9.4 years, reported that the supplementation with 500 mg daily of vitamin C had no effect on the occurrence of breast cancer [393]. However, in a cohort study including postmenopausal women, Cui and colleagues found a significant increased risk of breast cancer with high dose of vitamin C supplementation [120].

The safety of oral vitamin C supplements subsequent of the cancer diagnosis is not obvious [386]. The attention given to vitamin C is increasing since the publication of the in vitro study by Chen and collaborators [394] which verified the selective apoptosis of cancer cells induced by high concentrations of vitamin C. This effect was also supported by Ullah et al. [395]. Additionally, vitamin C enhances immunity and presents antioxidant properties including the neutralization of free radicals which may interfere with cancer progression [396]. The important issue is if these beneficial outcomes can be effective in vivo (i.e., in human body) considering the solubility of this vitamin and some parameters should be clarified, namely, the dose of vitamin C, the timing of supplementation, the side effects of high concentration of vitamin C (e.g., for kidneys), and its effect in combination with pharmacological and conventional cancer therapies (e.g., chemo- and radiotherapy). These properties are controversial and seem to be dependent on the dose, the source of vitamin C intake (i.e., derived from food or supplementation), and the timing and duration of intake [125, 397]. For example, some studies associated the dietary vitamin C intake with reduced risk of breast cancer mortality [125, 398] and no relationship demonstrated in other studies [26]. Additionally, the results also varied in the case of vitamin C supplementation. Studies reported inverse association between vitamin C supplementation, most of them referred to postdiagnosis breast cancer supplementation and mortality or recurrence [123, 126, 381], and no association was reported by Harris et al. [125]; however, this study presented a limited power analysis. These differences are probably related to the limitations of each study (i.e., small population with no confidence intervals or statistical analysis; details of concurrent treatment, heterogeneity across included studies). The relationship between vitamin C supplement intake and breast cancer risk was evaluated in an epidemiologic study with 57,403 postmenopausal women via food-frequency and supplement questionnaires. Vitamin C supplement was not associated with breast cancer risk overall but was associated with increased postmenopausal breast cancer risk in women with high vitamin C intake from foods [124].

Concerning the use of antioxidant supplements, including vitamin C, during conventional treatment of cancer, the evidence from experimental studies and observational or clinical trials is also controversial. Jacobs et al., since there is no high-quality evidence to confirm the benefits of vitamin supplementation in cancer patients (either increases the antitumour effects of chemotherapy or reduces its toxicity), do not recommend the use of this vitamin until double-blind placebo-controlled trials are completed [399]. Moreover, Subramani and collaborators verified that the pretreatment of MCF-7 breast cancer cells with vitamin C, in a dose-dependent reply, protected them against lipid peroxidation caused by tamoxifen treatment [400]. However, Hubner and Hanf suggested that the vitamin C from dietary sources does not have negative effects not only in chemo- and radiotherapy but also for targeted drugs [397]. Vitamin C (500 mg daily) supplementation in combination with vitamin E (400 mg daily) and tamoxifen therapy, for the period of 3 months, in postmenopausal women with breast cancer reduced the tamoxifen effect in plasma lipid and lipoprotein levels [127]. The tamoxifen therapy may enhance the synthesis of VLDL and diminish the activity of lipoprotein lipase which hydrolyses triglycerides [391]. A retrospective study showed fewer side effects of chemotherapy in breast cancer patients supplemented with low-dose infusion of vitamin C [401]; nonetheless this study did not refer to recurrence and survival data and conclusions about its safety could not be assessed. In a randomized 5-month study, Suhail and collaborators concluded that the supplementation of vitamin C (500 mg daily) and vitamin E (400 mg daily) restores antioxidant status, lowered by the breast cancer and chemotherapy, and reduces the DNA damage [128]. The authors also suggested that this regimen of supplementation should be helpful in protecting against the side effects associated with the cycles of chemotherapy treatments. Other studies reported similar conclusions after intravenous vitamin C administration [129, 130]. For example, Vollbracht et al. conducted a retrospective, multicentre, epidemiological cohort study which proved that the intravenous vitamin C administration improves quality of life in breast cancer patients during chemo/radiotherapy and aftercare [130]. In this context, the route (oral versus intravenous) used for vitamin C supplementation should also be considered when evaluating the efficacy and safety among cancer patients. Pharmacokinetic studies suggest that much higher levels of plasmatic vitamin C can be achieved by bypassing the oral route [402].

The dose of vitamin C supplementation varied in the breast cancer patients from 400 mg or less per day (in the Shanghai Breast Cancer Survival Study [381]) to higher than 1 g [403]. Development validated randomized trials are warranted to define if these higher amounts are safe and which dosage is required to reach the experimental concentrations described by Chen et al. [394]. Different levels of intake (from both dietary and supplementation) may influence the safety and efficacy in cancer patients [386]. Hoffer et al., in a dose-finding phase I study, demonstrated that the intravenous administration of ascorbic acid in a low-dose had inferior outcomes compared to patients supplemented with higher doses [404].

Ascorbic acid is a critical nutrient for the synthesis and integrity of collagen and for the optimal stability of the extracellular matrix which are essential factors for controlling cancer. Based on the presumption that cancer patients have low reserves of ascorbic acid [405], Cha and colleagues showed that the supplementation of ascorbate in ascorbate-restricted mice injected with breast cancer cells reduced tumour growth and enhanced encapsulation of tumours [406]. Additionally, it modulated inflammatory cytokine secretion. These results support the proposed approach of using vitamin C to treat the cancer [407]. The administration of intratumoural vitamin C delayed tumour growth in murine solid tumour models and synergistic antitumour effects were observed with cisplatin [408]. However, this study was performed on animals. So, the use of vitamin C as anticancer therapy is not recommended in cancer patients.