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| Caloric restriction mimetics (CRMs) Examples of the most studied CRM and their anti-cancer effects include metformin, rapamycin, aspirin, and resveratrol and its by-products. Calorie Restriction Mimetics — Calorie restriction mimetics (CRMs) are a mechanistic class of compounds intended to reproduce selected biochemical effects of caloric restriction without requiring sustained energy restriction. They are best viewed as a research/therapeutic concept rather than a single drug entity or a formally approved regulatory class. Standard abbreviation: CRM or CRMs. In the oncology literature, the most commonly cited CRMs are metformin, rapamycin or rapalogs, aspirin or salicylate, resveratrol, spermidine, and hydroxycitrate; broader candidate lists often also include EP300-inhibitory or sirtuin-linked dietary compounds such as curcumin, garcinol, anacardic acid, EGCG, and some synthetic sirtuin activators. Their shared functional identity is partial imitation of nutrient-deprivation signaling, especially autophagy induction, lowered protein acetylation, AMPK-SIRT engagement, and relative suppression of anabolic growth signaling. In practice, however, CRM biology is highly heterogeneous, agent-specific, and often limited by pharmacokinetics, dose ceilings, or context-dependent tumor effects. Primary mechanisms (ranked):
Bioavailability / PK relevance: PK is not class-uniform. Metformin is orally available but hydrophilic and tissue-distribution dependent; rapamycin is orally active but shows variable exposure and clinically important immunosuppressive toxicity; aspirin is systemically available but dose-limited by bleeding risk; resveratrol has poor oral bioavailability and rapid metabolism; spermidine supplementation can show only modest increases in circulating polyamines because of strong homeostatic control. Many “dietary CRM” candidates therefore have more convincing mechanistic than translational PK support. In-vitro vs systemic exposure relevance: This is a major translation issue for the class. Many in-vitro CRM studies use concentrations that are not cleanly achievable in human plasma or tumors, especially for metformin and several polyphenols such as resveratrol. Accordingly, class-level conclusions should prioritize pathway directionality and combination/adjunct effects over direct cytotoxicity observed at high in-vitro doses. Clinical evidence status: Mixed and agent-dependent. For cancer, CRM evidence is strongest at the preclinical and adjunct-mechanistic level. Human data exist mainly for individual agents such as metformin, aspirin, and rapalogs rather than for “CRMs” as a validated class, and results remain heterogeneous across tumor types and trial designs. At present, CRMs are better regarded as a translational framework and combination strategy than as an established standalone oncology therapy category. CRM Product/Priority Table
Mechanistic Pathway Table
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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 |
| 5798- | CRMs, | Caloric restriction mimetics improve gut microbiota: a promising neurotherapeutics approach for managing age-related neurodegenerative disorders |
| - | Review, | Nor, | NA | - | Review, | AD, | 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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