∗School of Biotechnology and Bioengineering, Sungkyunkwan College, Suwon, 16419, Republic of Korea
†Yeom Chang-Hwan Hospital, Seoul, 06605, Republic of Korea
∗School of Biotechnology and Bioengineering, Sungkyunkwan College, Suwon, 16419, Republic of Korea
‡Division of Utilized Chemistry, Dongduk Ladies’s College, Seoul, 02748, Republic of Korea
§Division of Well being Sciences and Expertise, Samsung Superior Institute for Well being Sciences and Expertise, Sungkyunkwan College, Seoul, 06351, Republic of Korea
∗School of Biotechnology and Bioengineering, Sungkyunkwan College, Suwon, 16419, Republic of Korea
∗School of Biotechnology and Bioengineering, Sungkyunkwan College, Suwon, 16419, Republic of Korea
∗School of Biotechnology and Bioengineering, Sungkyunkwan College, Suwon, 16419, Republic of Korea
‡Division of Utilized Chemistry, Dongduk Ladies’s College, Seoul, 02748, Republic of Korea
∗School of Biotechnology and Bioengineering, Sungkyunkwan College, Suwon, 16419, Republic of Korea
†Yeom Chang-Hwan Hospital, Seoul, 06605, Republic of Korea
Summary
Introduction
Excessive-dose l-ascorbic acid (vitamin C, AA) most cancers remedy was launched by Linus Pauling and Ewan Cameron [[1], [2], [3]]. Scientific demonstration outcomes by Pauling and Cameron confirmed that intravenous injection of 10 g/day of vitamin C prolonged the survival time of terminal most cancers sufferers by about 4.2 instances. Nevertheless, outcomes from the Mayo Clinic confirmed that the survival time of vitamin C–handled sufferers was even shorter than that of the placebo group sufferers [4]. A major distinction between these two analysis teams was the route of AA administration: intravenous injection and oral administration, respectively. To grasp the mechanism of AA’s anticancer exercise, many analysis teams have handled colon, prostate, leukemia, lymphoma, mind, and abdomen most cancers cells and chemically or genetically remodeled most cancers cells with AA and confirmed most cancers progress inhibition and even most cancers cell demise by way of hydrogen peroxide–mediated reactive oxygen species (ROS) technology [[5], [6], [7], [8], [9], [10], [11]]. Most often, the pharmacological focus of vitamin C required for anticancer results (EC50 worth of 1–10 mM) might solely be achieved by intravenous administration [12]. Thus, to use [13] vitamin C as an anticancer remedy, a excessive intracellular focus in most cancers cells is critically essential.
In our earlier research, we investigated the hormetic proliferation response of most cancers cell traces with low mobile expression ranges of sodium-dependent vitamin C transporter family-2 (SVCT-2). When a low dose of vitamin C was delivered into such most cancers cells, elevated proliferation exercise was noticed [13]. As a result of hormetic proliferation of most cancers cells occurred on low-dose remedy with vitamin C in cell traces with low SVCT-2 expression, we have to develop a simpler strategy for vitamin C anticancer remedy in cells that specific little SVCT-2. The shut correlation between SVCT-2 expression and the anticancer results of vitamin C remedy means that SVCT-2, which is a key transporter for vitamin C uptake [14,15], may very well be a potent biomarker for high-dose vitamin C most cancers remedy [16]. In breast and colon most cancers cell traces, the anticancer impact of vitamin C confirmed a constructive correlation between the SVCT-2 expression of the most cancers cells and intracellular vitamin C focus [16].
To forestall a hormetic response throughout vitamin C remedy and induce vitamin C most cancers remedy extra successfully, magnesium ion supplementation was advisable to extend the vitamin C uptake exercise of SVCT-2 [17]. Myer’s cocktail, which comprises nutritional vitamins and mineral mixtures (together with magnesium ions), was developed to be used with intravenous vitamin C injections [[18], [19], [20]], and it has been broadly utilized in clinics [21,22].
When Myer’s cocktail was first launched, no data was out there in regards to the relationship between magnesium ions and SVCT-2 exercise. Subsequently, we now have centered on utilizing magnesium ion supplementation with vitamin C most cancers remedy to stop the hormetic response in most cancers cell traces with low SVCT-2 ranges. On this research, we demonstrated that including magnesium ions to the vitamin C answer enhanced the anticancer results of vitamin C by rising the vitamin C transport exercise of SVCT-2 in most cancers cell traces with each excessive and low ranges of SVCT-2. Furthermore, our outcomes present that including magnesium supplementation to vitamin C most cancers remedy might present simpler most cancers remedy and forestall the hormetic response in most cancers cells with low SVCT-2 ranges.
Supplies and Strategies
Outcomes
Dialogue – “magnesium and vitamin c”
Our earlier research demonstrated a hormetic proliferation response to low-dose vitamin C in most cancers cell traces with low SVCT-2 expression [13]. Subsequently, we screened the approaches noticed to stop that hormetic response in earlier work [13]. One potent strategy was remedy with magnesium ions and vitamin C collectively as a result of magnesium had already been reported as an activator of SVCT-2, which is a vitamin C transporter [17]. Godoy et al. (2006) demonstrated that Ca2+ and Mg2+ supplementation switched the inactive type of SVCT-2 into the lively type of SVCT-2 by rising the Vmax worth of SVCT-2 itself. Subsequently, we utilized magnesium ion supplementation to vitamin C most cancers remedy. On this research, we discovered that magnesium supplementation (each MgSO4 and MgCl2) elevated the mobile uptake of vitamin C in most cancers cells by way of activation of SVCT-2. Furthermore, ROS technology by way of dihydrogen peroxide [12,24,25] additionally elevated as a result of extra vitamin C collected within most cancers cells when magnesium was added to vitamin C remedy. This prooxidant exercise of vitamin C led to the breakage of mobile DNA, which interrupted the redox steadiness and ultimately altered the mobile metabolism of most cancers cells, resembling vitality metabolism by way of NAD depletion [26,27]. Collectively, the robust correlation between this anticancer mechanism of vitamin C and the hormetic response of most cancers cells to vitamin C signifies that the quantity of mobile uptake of vitamin C may be an essential examine within the utility of vitamin C to most cancers remedy.
Magnesium ion supplementation elevated the mobile uptake of vitamin C and enhanced the anticancer results of vitamin C in each in vitro and in vivo programs (Determine 2, Determine 8). Moreover, the hormetic proliferation response was inhibited when a magnesium complement was added to vitamin C remedy within the SK-BR-3 cell line, which has low SVCT-2 expression (Determine 7). Each MgSO4 and MgCl2 confirmed an enhanced anticancer impact when added to vitamin C remedy, however MgCl2 confirmed barely higher results than MgSO4 each in vitro and within the xenograft. Maybe, MgCl2 is taken into cells higher than MgSO4 [28,29]. Different research have revealed that MgCl2 interacts with all of the exchangers within the cell membrane, whereas MgSO4 impacts solely paracellular parts [[30], [31], [32]]. Subsequently, we advise that extra magnesium ions fluxed into cells by way of elevated SVCT-2 exercise when MgCl2 was used than when MgSO4 was used.
Myers’ cocktail, which incorporates MgCl2 and vitamin C, has been used as an auxiliary to high-dose vitamin C most cancers remedy [[18], [19], [20]]. Nevertheless, the impact of every ingredient (magnesium chloride, calcium gluconate, hydroxocobalamin, pyridoxine hydrochloride, dexpanthenol B advanced) of Myers’ cocktail on most cancers cells has not been totally investigated. Subsequently, we’re right here the primary to disclose that the magnesium ions in Myers’ cocktail are a synergistic anticancer agent with vitamin C remedy.
Numerous chemotherapeutic brokers with vitamin C have been examined as most cancers remedy [33,34]. In lots of experiences, vitamin C alleviated the unintended effects of and supplied synergistic results with anticancer medicine [[35], [36], [37], [38], [39]]. Nevertheless, some experiences have claimed that vitamin C is noneffective as an anticancer remedy [4,40] and even that it has adversarial results on sufferers [35,41]. Amongst a number of prospects for the damaging results attributable to vitamin C anticancer remedy in sufferers, we centered on the hormetic proliferation response attributable to low mobile uptake of vitamin C even when excessive doses of vitamin C got. In our earlier work [13], we demonstrated {that a} low expression degree of SVCT-2 might trigger a hormetic response to vitamin C anticancer remedy. Right here, we advise that the activation of SVCT-2 by magnesium supplementation given together with vitamin C, with out de novo induction of SVCT-2, might forestall the hormetic response proven in most cancers cells with low expression ranges of SVCT-2. Though magnesium ions have been extensively utilized in vitamin C remedy as a element of Myers’ cocktail, the synergistic anticancer results of vitamin C and magnesium ions are first reported by this analysis to consequence from the activation of SVCT-2. Our outcomes additionally recommend that magnesium ion supplementation, resembling MgCl2 or MgSO4, is a gorgeous cofactor that would enhance the anticancer results of vitamin C remedy (Determine 9).
Competing Pursuits
The authors declare no competing pursuits.
References