How long does dca take to work

This is done until the end value of the portfolio is reached. As you can see in this example below, you have invested less as the price has risen, and the opposite would be true if the price had fallen.

Therefore, instead of investing a set amount each period, a VA strategy makes investments based on the total size of the portfolio at each point. Below is an expanded example comparing the two strategies:. The chart above indicates that a majority of shares are purchased at low prices. When prices drop and you put more money in, you end up with more shares. This happens with DCA as well, but to a lesser extent. Most of the shares have been bought at very low prices, thus maximizing your returns when it comes time to sell.

If the investment is sound, VA will increase your returns beyond dollar cost averaging for the same time period and at a lower level of risk. In certain circumstances, such as a sudden gain in the market value of your stock or fund, value averaging could even require you to sell some shares sell high, buy low.

Overall, value averaging is a simple, mechanical type of market timing that helps to minimize some timing risk. In using DCA, investors always make the same periodic investment. The only reason they buy more shares when prices are lower is that the shares cost less.

In contrast, with VA investors buy more shares because prices are lower, and the strategy ensures that the bulk of investments are spent on acquiring shares at lower prices. VA requires investing more money when share prices are lower and restricts investments when prices are high, which means it generally produces significantly higher investment returns over the long term. All risk-reduction strategies have their tradeoffs , and DCA is no exception. First of all, you run the chance of missing out on higher returns if the investment continues to rise after the first investment period.

Also, if you are spreading a lump sum, the money waiting to be invested doesn't garner much of a return by just sitting there. Still, a sudden drop in prices won't impact your portfolio as much as if you had invested all at once. Some investors who engage in DCA will stop after a sharp drop, cutting their losses; however, these investors are actually missing out on the main benefit of DCA—the purchase of larger portions of stock more shares in a declining market—thereby increasing their gains when the market rises.

When using a DCA strategy, it is important to determine whether the reason behind the drop has materially impacted the reason for the investment. If not, then you should stick to your guns and pick up the shares at an even better valuation. Another issue with DCA is determining the period over which this strategy should be used. You can click "Auto-fill with" to populate online forms with information from registered accounts, saving time.

If you are a business, you can link your account to all of your DCA records. You can have multiple user accounts link to your DCA records. If multiple user accounts are linked to multiple records, DCA encourages you to:. Businesses can also ask questions using our online Live Chat , from a. Monday through Friday.

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How long does it take to process an application? If all requirements are complete and satisfactory, we will generally issue a license within two weeks. We strongly encourage you to prepare your application well in advance of when you want to start operating because operating without a current license could result in a violation and fines.

An increasing body of literature supports the detection, among natural compounds, of biologically active substances isolated by plants, mushrooms, and bacteria or marine organism that show beneficial effects for human health [ 46 — 48 ].

The assumption of natural compounds or their derivatives seems to represent an encouraging approach to prevent cancer initiation or recurrence, and it is generally called chemoprevention [ 49 ].

Moreover, natural substances produce beneficial effects in cancer therapy when coadministered with other drugs, showing their ability to overcome drug resistance, to increase anticancer potential, and to reduce drug doses and toxicity [ 50 , 51 ]. Interestingly, the coadministration of DCA and natural compounds has been recently purposed. A study investigated the combined effect of DCA with essential oil-blended curcumin, a compound with beneficial properties both in prevention and treatment of cancer [ 52 ], demonstrating an anticancer potential against HCC [ 53 ].

In particular, the combination of both compounds synergistically reduced cell survival, promoting cell apoptosis and inducing intracellular ROS generation. Betulin, a natural compound isolated from birch bark, is already known for its antiproliferative and cytotoxic effects against several cancer cell lines [ 54 — 56 ]. Radiotherapy represents a further strategy to treat cancer and provides a local approach by the administration of high-energy rays [ 58 ].

The main effect of radiation is the induction of ROS with a consequent DNA damage, chromosomal instability, and cell death by apoptosis [ 59 ].

However, several tumours show or develop radioresistance that is responsible for radiotherapy failure and high risk of tumour recurrence or metastasis [ 60 ]. Several factors may be responsible of radioresistance [ 61 ]. Among these, hypoxia, a common condition of tumour microenvironment characterized by low oxygen levels and reduced ROS species generation, can block the efficacy of ionizing radiations [ 62 ].

Increasing tumour oxygenation so to favour a considerable amount of ROS [ 63 ] or directly induce ROS production may therefore represent a strategy to increase radiosensitization [ 64 , 65 ]. In this setting, DCA administration, known to induce ROS production [ 11 , 66 ], could represent a strategy to overcome tumour radioresistance. Moreover, metabolic alterations featuring cancer development are known to affect radiosensitivity [ 67 , 68 ].

Therefore, targeting cancer metabolic intermediates may represent a strategy to improve a selective cancer response to irradiation [ 69 ]. The efficacy of DCA to increase radiation sensitivity has been already demonstrated both in glioblastoma cells [ 70 ] and in oesophageal squamous cell carcinoma [ 71 ]. More recently, it was demonstrated that DCA increases radiosensitivity in a cellular model of medulloblastoma, a fatal brain tumour in children, inducing alterations of ROS metabolism and mitochondrial function and suppressing DNA repair capacity [ 72 ].

Since the role of immunotherapy in the restoration of the immune defences against tumour progression and metastasis is arousing great attention in the last years [ 73 ], Gupta and Dwarakanath provided a state of the art of the possible effects of glycolytic inhibitors, including DCA, on tumour radiosensitization, focusing their attention on the interplay between metabolic modifiers and immune modulation in the radiosensitization processes [ 74 ].

Interestingly, they reported the ability of DCA to promote immune stimulation through the inhibition of lactate accumulation, further sustaining its utilization as adjuvant of radiotherapy. There is a growing interest in designing new drug formulations so to improve drug delivery, increasing the efficacy and reducing the doses and consequently undesirable effects.

In this setting, drug delivery systems DDSs represent a new frontier in the modern medicine [ 75 ]. DDSs offer the possibility to create a hybrid of metal-organic frameworks MOFs , combining the biocompatibility of organic system to the high loadings of inorganic fraction [ 76 ]. Several lines of evidence suggest an efficient functionalization of nanoparticles with DCA. Lazaro and colleagues [ 77 ] explored different protocols for DCA functionalization of the zirconium Zr terephthalate UiO nanoparticles.

They demonstrated the cytotoxicity and selectivity of the same DDSs against different cancer cell lines. The same group later showed the possibility to load Zr MOFs with a second anticancer drug, such as 5-fluorouracil 5-FU , so to reproduce the synergistic effect of the two drugs [ 78 ]. Zirconium-based MOF loaded with DCA was also purposed as an attractive alternative to UiO, showing selective in vitro cytotoxicity towards several cancer cell lines and a good toleration by the immune system of several species [ 79 ].

Both Ru-dca and Os-DCA complexes were screened in ovarian carcinoma cell lines, demonstrating to be more cytotoxic than cisplatin alone. Both complexes were able to induce cytochrome c Cytc release from mitochondria, an indirect index of apoptosome activation and seemed to be less toxic towards healthy primary human hepatocytes, thus indicating selectivity for cancer over noncancerous cells. Promising results were also obtained in triple-negative breast cancer cells [ 81 ].

Rhenium I -DCA conjugate has demonstrated an efficient penetration into cancer cells and a selective accumulation into mitochondria, inducing mitochondrial dysfunction and metabolic disorders [ 82 ]. In the recent years, several multiactive drugs have been designed to contemporary target different intracellular pathways using a single formulation.

A safe, simple, reproducible nanoformulation of the complex doxorubicin-DCA Figure 2 b was successfully tested in a murine melanoma model, showing an increase in drug-loading capability, lower side effects, and enhanced therapeutic effect [ 83 ]. Dual-acting antitumor Pt IV prodrugs of kiteplatin with DCA axial ligands have been synthesized Figure 2 c , characterized, and tested in different tumour cell lines and in vivo [ 84 ]. To overcome cancer resistance, triple action Pt IV derivatives of cisplatin have been proposed as new potent anticancer agents, able to conjugate the action of cisplatin, cyclooxygenase inhibitors, and DCA Figure 2 d [ 85 ].

Authors demonstrated the ability of such a prodrug to affect energy metabolism, to promote apoptosis, and to interact with DNA. The high selectivity of biotin for cancer cells minimizes the detrimental effects on normal cells and improves the curative effect on tumours [ 86 ].

Features and experimental evidence of the main classes of compounds are summarized in Table 3. The metabolic shift from glycolysis to glucose oxidation due to the inhibition of PDK and the consequent activation of PDH is the best-known and well-accepted molecular effect of DCA administration. The consequent biochemical alterations, including ROS increase and mitochondrial membrane potential variation, may be responsible for proliferation arrest and cancer cell death, thus explaining DCA beneficial potential in cancer treatment [ 9 ].

However, the molecular intermediates activated after DCA administration are still unknown. It is conceivable that such a small molecule might directly or indirectly affect other cellular and molecular targets Figure 3 , displaying other mechanisms of action, so to explain its efficacy also in cellular models where it does not produce the expected metabolic shift [ 12 ].

A proteomic approach applied to cells of lung cancer demonstrated the ability of DCA to increase the concentration of every TCA intermediate while it did not affect glucose uptake or the glycolytic process from glucose to pyruvate [ 87 ]. In the attempt to shed light to DCA mode of action, Dubuis and colleagues used a metabolomics-based approach on several ovarian cancer cell lines treated with DCA and found a common marked depletion of intracellular pantothenate, a CoA precursor, as well as a concomitant increase of CoA, thus suggesting DCA ability to increase CoA de novo biosynthesis.

Since high concentrations of CoA resulted to be toxic for cells, this metabolic effect could be responsible of cancer cell toxicity mediated by DCA [ 88 ]. A very recent work by El Sayed et al.

Moreover, high acetate levels are associated to anticancer drug resistance [ 90 ]. It has been shown that DCA is able to revert metabolic alterations induced by acetate by restoring physiological serum levels of lactate and free fatty acid and potassium and phosphorus concentration. According to the authors, thanks to a structural similarity to acetate, DCA could inhibit metabolic effects driven by acetate, responsible for cancer cell growth and chemoresistance [ 89 ].

Another possible additional effect of DCA could be pH modulation. DCA treatment may both increase and reduce intracellular pH. A secondary effect of pyruvate redirecting into the mitochondria by DCA would be lactate reduction and a consequent increase in intracellular pH. On the other side, DCA is able to decrease the expression of monocarboxilate transporters and V-ATPase with a consequent reduction of pH, and this especially occurs in tumour cells, expressing higher amount of these carriers, compared to normal counterparts [ 93 ].

Given the ability to induce rapid tumour intracellular acidification, Albatany et al. Animal models allow to identify a possible further molecular target of DCA.

As NKCC is an important biomarker of extracellular and intracellular ion homeostasis regulation and participates in cell cycle progression, it plays an important role in cancer cell proliferation, apoptosis, and invasion.

Belkahla et al. The resulting reduction of Oct4 transcription levels was associated to a reduction of stemness phenotype and a significant increased sensitivity to cell stress. There is a growing interest in targeting cancer stem cells CSCs which seem to be the main responsible for tumour relapse [ ]. CSCs share the ability of self-renewal with normal stem cells and can give rise to differentiating cells, responsible for tumour initiation as well as malignant progression [ ].

A low proliferation rate and specific metabolic profile contribute to make CSCs resistant to conventional chemotherapy [ ]. An urgent need emerged in the developing of new therapeutic agents able to affect cancer stem cell viability [ ] in order to completely eradicate the tumour mass. An extensive body of literature is focusing the attention on the metabolic phenotype of CSCs, which seem to differ from differentiated cancer cells and could represent a therapeutic target [ — ].

In this setting, the possible sensitivity of CSC fraction to DCA has been hypothesized and tested in different cancer models. Embryonal carcinoma stem cells represent one of the more appropriate models for the study of CSC maintenance and differentiation and the identification of drugs and molecules able to modulate these processes [ ].

Studies performed on embryonic stem cells ESCs constitute preliminary important proofs supporting a possible efficacy of DCA [ ]. Interestingly, DCA treatment of ESCs promotes loss of pluripotency and shifts towards a more active oxidative metabolism, accompanied by a significant decrease in HIF1a and p53 expression [ ].

Vega-Naredo et al. They characterized the metabolic profile of stem cell fraction and guessed the less susceptibility of stem phenotype to mitochondrial-directed therapies. Several reports support the existence of CSCs in glioma [ , ], and the efficiency of DCA to hit CSCs has been extensively evaluated in such a cancer type, so difficult to treat with conventional therapies and characterized by low rates of survival.

Already in , Michelakis and colleagues had suggested, both in vitro and in vivo , DCA ability to induce apoptosis of cancer stem cell fraction [ 26 ].

A rat model of glioma, recapitulating several features of human glioblastoma, confirmed the efficacy of DCA to potentiate apoptosis of glioma CSCs, characterized by a significant glycolytic pathway overstimulation, compared to normal stem cells [ ]. Also, Jiang et al. Moreover, an in vivo test on mice bearing DCA-treated GSC-derived xenografts showed a significant increase in overall survival.

DCA treatment was also tested in melanoma stem cell fraction, and the derived bioenergetics modulation was able to counteract protumorigenic action of a c-Met inhibitor [ ]. A very recent work performed on human hepatocellular carcinoma identified PDK4 overexpression in spheres originated from cancer cells, featuring a defined stem-like phenotype. Interestingly, DCA treatment was able to reduce cell viability both of cancer-differentiated cells and cancer stem cells and reversed chemoresistance to conventional therapy [ 36 ].

Together with chemoresistance, also radioresistance represents a limit to an efficient cancer treatment, and CSCs seem to be responsible for such refractoriness [ ].

Sun et al. Moreover, in the same cellular model, they showed an altered mechanism of DNA repair induced by DCA able to explain the increased effectiveness of radiotherapy. Targeting cancer cell metabolism represents a new pharmacological approach to treat cancer. DCA ability to shift metabolism from glycolysis to oxidative phosphorylation has increased the interest towards this drug already known for its anticancer properties.

The evidence accumulated in the last years confirms the capability of DCA to overcome chemo, radioresistance in several cancer types and lets to hypothesize additional cellular targets able to explain its skill to kill cancer cells. There is a need to design further clinical studies now limited to poor-prognosis patients with advanced, recurrent neoplasms, already refractory to other conventional therapies. Its potential efficacy against cancer stem cells as well as the development of new drug formulations takes us closer to reach an effective clinical employment of DCA.

This is an open access article distributed under the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Article of the Year Award: Outstanding research contributions of , as selected by our Chief Editors. Read the winning articles. Journal overview. Special Issues. Guest Editor: Kanhaiya Singh. Received 24 Jul Revised 12 Sep Accepted 11 Oct Published 14 Nov Abstract An extensive body of literature describes anticancer property of dichloroacetate DCA , but its effective clinical administration in cancer therapy is still limited to clinical trials.

Introduction Cancer is one of the leading causes of death worldwide. Figure 1. Table 1. List of reports suggesting beneficial effect of DCA and chemotherapy coadministration in several types of cancers.

Table 2. List of drugs with their main function tested in combination with DCA in several cancer models. Figure 2. New drug formulations containing DCA. Table 3. Properties of the main classes of DCA drug formulations tested in cancer cell lines and in vivo models with experimental evidence related. Figure 3. Other proposed mechanisms of action of DCA. DCA also increases each Krebs cycle intermediate concentration 2 [ 87 ].

DCA induces cell toxicity via de novo synthesis of CoA 3 [ 88 ]. DCA may antagonize acetate 4 [ 90 ]. DCA modulates intracellular acidification 5 [ 93 , 94 ]. DCA reduces the expression of self-renewal-related genes and affects cancer stem cell fraction 8 [ 99 ]. References T. Lee, E. Jeong, I. Min, S. Kim, H. Kim, and C. November 8, There's tons of advice about how big your nest egg should be for retirement but focusing too much on a single figure can lead to complacency.

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