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| HCA is a naturally occurring compound primarily known for its potential effects on appetite and lipid metabolism via inhibition of ATP citrate lyase. 1,2-dihydroxy-1,2,3-propanetricarboxylic acid, structurally a hydroxy derivative of citric acid Derivative of citric acid that is found in a variety of tropical plants including Garcinia cambogia and Hibiscus sabdariffa Hydroxycitric acid (HCA) is best known for inhibiting ATP citrate lyase (ACLY), a key enzyme that generates cytosolic acetyl-CoA from citrate for lipid and cholesterol synthesis. By reducing ACLY activity and downstream lipogenesis, HCA shifts cellular metabolism and can activate energy-sensing pathways (such as AMPK) in some models. Evidence for direct anticancer cytotoxicity is modest and often linked to metabolic stress rather than primary cytotoxic mechanisms. Oral exposure is influenced by rapid metabolism and conjugation, with systemic bioavailability often limited compared to levels used in many in vitro studies. • Hydroxy-Citric Acid (HCA) is a compound extracted from Garcinia cambogia, primarily recognized for its potential effects on lipid metabolism and appetite suppression. • It has been proposed to inhibit the enzyme ATP citrate lyase, which is involved in converting citrate into acetyl-CoA—a key step in fatty acid synthesis. • By modulating lipid synthesis pathways, HCA has been studied in the context of obesity and metabolic disorders, with some exploratory research considering its implications in cancer metabolism. • Inhibition of ATP Citrate Lyase (ACLY)****** ACLY converts citrate into acetyl-CoA, a building block for fatty acid and cholesterol synthesis. Many cancer cells upregulate lipid synthesis to support membrane production and energy storage; hence, inhibiting ACLY presents a potential strategy to disrupt cancer cell metabolism. • Impact on Lipogenesis Reduced acetyl-CoA production can impair de novo lipogenesis, potentially limiting the proliferation of rapidly dividing cells that have high lipid demands. • Interactions with Other Metabolic Pathways (modulation of citrate levels may affect the TCA cycle) -Dosages used in weight loss studies typically ranging from 500 mg to 1500 mg per day Human cyclists: 3.1 mL/kg body wt of an HCA solution (19 g/L) --> 248mg "Studies have shown that humans can safely ingest 13.5 g of hydroxycitrate per day with plasma levels of 82 mg/L (0.39 mM) achieved". Appetite suppression and weight loss effects are mixed. Typically, HCA used in dietary weight loss supplement is bound to calcium, which results in a poorly soluble (<50%) and less bioavailable form. Conversely, the structural characteristics of a novel Ca2+/K+ bound (-)-HCA salt (HCA-SX or Super CitriMax) make it completely water soluble as well as bioavailable. -HydroxyCitrate (HCA) typically used in a dose of about 1.5g/day(experimental) or more for cancer (inhibition of the Melavonate Pathway?) Hydroxycitric Acid — Hydroxycitric acid (HCA), particularly the naturally occurring (−)-hydroxycitric acid stereoisomer, is a plant-derived hydroxytricarboxylic acid structurally related to citric acid and best known as a competitive inhibitor of ATP citrate lyase (ACLY). It is classified as a natural small-molecule metabolic modulator and nutraceutical ingredient. The standard abbreviation is HCA. Major botanical sources include the fruit rind of Garcinia gummi-gutta (syn. Garcinia cambogia) and related Garcinia species; commercial preparations commonly supply calcium, potassium, or calcium/potassium hydroxycitrate salts. By limiting ACLY-dependent production of cytosolic acetyl-CoA, HCA can reduce de novo fatty-acid and cholesterol synthesis. Its anticancer evidence is predominantly preclinical and metabolic rather than evidence of clinically established tumor-selective cytotoxicity. Primary mechanisms (ranked):
Bioavailability / PK relevance: HCA is orally absorbed, but exposure depends strongly on formulation and food intake. Calcium-only salts have relatively poor solubility, whereas calcium/potassium salts are more water soluble. In a human Phase I crossover study, food reduced HCA peak plasma exposure approximately threefold and total exposure approximately twofold, with substantial inter-individual variability. Earlier human measurements after a 2-g oral dose found plasma concentrations of approximately 0.8–8.4 µg/mL. Consequently, formulation, dose timing, and fed versus fasting state materially affect systemic exposure. In-vitro vs systemic exposure relevance: Many mechanistic cancer experiments use HCA concentrations substantially above plasma concentrations produced by ordinary supplement doses. Oral HCA can reach systemic circulation, but millimolar concentrations used in some cell-culture studies are generally difficult to reproduce with conventional nutritional dosing. Exceptionally high oral exposures have reportedly produced substantially higher plasma concentrations, but these should not be treated as equivalent to routine supplement use. Translation of direct in-vitro anticancer effects to standard oral dosing is therefore uncertain. Clinical evidence status: Cancer: primarily preclinical, including cell culture and xenograft/animal studies; limited exploratory human combination experience exists, but there is no established randomized evidence demonstrating HCA as an anticancer treatment. Metabolic/weight management: multiple human randomized trials and systematic reviews exist, but overall weight-loss benefit is small and inconsistent. HCA is marketed as a natural health/dietary supplement rather than an approved cancer drug. Health Canada recognizes calcium/potassium hydroxycitrate as a natural health product ingredient for temporary enhancement of satiety, not for cancer treatment. Safety / translation: Short-term controlled studies generally report tolerability, but gastrointestinal adverse effects occur and post-marketing literature contains cases of clinically significant liver injury associated with Garcinia/HCA-containing products, including rare severe hepatic failure. Attribution can be difficult because many reports involve botanical extracts or multi-ingredient products; however, recent reviews consider a causal relationship plausible in at least a subset of cases. HCA should therefore not be characterized as uniformly non-toxic, particularly with prolonged or high-dose supplementation. Hydroxycitric Acid Cancer-Relevant Mechanisms
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| Source: TCGA |
| Type: Antiapoptotic |
| Nrf2 is responsible for regulating an extensive panel of antioxidant enzymes involved in the detoxification and elimination of oxidative stress. Thought of as "Master Regulator" of antioxidant response. -One way to estimate Nrf2 induction is through the expression of NQO1. NQO1, the most potent inducer: SFN 0.2 μM, quercetin (2.5 μM), curcumin (2.7 μM), Silymarin (3.6 μM), tamoxifen (5.9 μM), genistein (6.2 μM ), beta-carotene (7.2μM), lutein (17 μM), resveratrol (21 μM), indol-3-carbinol (50 μM), chlorophyll (250 μM), alpha-cryptoxanthin (1.8 mM), and zeaxanthin (2.2 mM) 1. Raising Nrf2 enhances the cell's antioxidant defenses and ↓ROS. This strategy is used to decrease chemo-radio side effects. 2. Downregulating Nrf2 lowers antioxidant defenses and ↑ROS. In cancer cells this leads to DNA damage, and cell death. 3. However there are some cases where increasing Nrf2 paradoxically causes an increase in ROS (cancer cells). Such as cases of Mitochondial overload, signal crosstalk, reductive stress -In some cases, Nrf2 is overexpressed in cancer cells, which can lead to the activation of genes involved in cell proliferation, angiogenesis, and metastasis. This can contribute to the development of resistance to chemotherapy and targeted therapies. -Increased Nrf2 expression: Lung, Breast, Colorectal, Prostrate. Decreased Nrf2 expression: Skine, Liver, Pancreatic. -Nrf2 is a cytoprotective transcription factor which demonstrated both a negative effect as well as a positive effect on cancer - "promotes Nrf2 translocation from the cytoplasm to the nucleus," means facilitates the movement of Nrf2 into the nucleus, thereby enhancing the cell's antioxidant and cytoprotective responses. -Major regulator of Nrf2 activity in cells is the cytosolic inhibitor Keap1. Nrf2 Inhibitors and Activators Nrf2 Inhibitors: Brusatol, Luteolin, Trigonelline, VitC, Retinoic acid, Chrysin Nrf2 Activators: SFN, OPZ EGCG, Resveratrol, DATS, CUR, CDDO, Api - potent Nrf2 inducers from plants include sulforaphane, curcumin, EGCG, resveratrol, caffeic acid phenethyl ester, wasabi, cafestol and kahweol (coffee), cinnamon, ginger, garlic, lycopene, rosemany Nrf2 plays dual roles in that it can protect normal tissues against oxidative damage and can act as an oncogenic protein in tumor tissue. – In healthy tissues, NRF2 activation helps protect cells from oxidative damage and maintains cellular homeostasis. – In many cancers, constitutive activation of NRF2 (often through mutations in NRF2 itself or loss-of-function mutations in KEAP1) leads to an enhanced antioxidant capacity. – This upregulation can promote tumor cell survival by enabling cancer cells to thrive under oxidative stress, resist chemotherapeutic agents, and sustain metabolic reprogramming. – Elevated NRF2 levels have been implicated in promoting tumor growth, metastasis, and resistance to therapy in various malignancies. – High or sustained NRF2 activity is frequently associated with aggressive tumor phenotypes, poorer prognosis, and decreased overall survival in several cancer types. – While its activation is essential for protecting normal cells from oxidative stress, aberrant or sustained NRF2 activation in tumor cells can lead to enhanced survival, therapeutic resistance, and tumor progression. NRF2 inhibitors: (to decrease antioxidant defenses and increase cell death from ROS). -Brusatol: most cited natural inhibitors of Nrf2. -Luteolin: luteolin can reduce Nrf2 activity in specific cancer models and may enhance cell sensitivity to chemotherapy. However, luteolin is also known as an antioxidant, and its influence on Nrf2 can sometimes be context dependent. -Apigenin: certain studies to down‑regulate Nrf2 in cancer cells: Dose and context dependent . -Oridonin: -Wogonin: although its effects might be cell‑ and dose‑specific. - Withaferin A |
| 1635- | HCA, | Hydroxycitric acid prevents hyperoxaluric-induced nephrolithiasis and oxidative stress via activation of the Nrf2/Keap1 signaling pathway |
| - | vitro+vivo, | Nor, | NA |
Query results interpretion may depend on "conditions" listed in the research papers. Such Conditions may include : -low or high Dose -format for product, such as nano of lipid formations -different cell line effects -synergies with other products -if effect was for normal or cancerous cells
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