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| Doxorubicin, (brand name Adriamycin) is a chemotherapy medication used to treat breast cancer, bladder cancer, Kaposi's sarcoma, lymphoma, and acute lymphocytic leukemia. Often used together with other chemotherapy agents. Given by injection into a vein. Doxorubicin is an anthracycline chemotherapy whose core anticancer activity is driven by DNA intercalation and topoisomerase II poisoning (DNA double-strand break stress), with additional contributions from redox cycling/iron-linked oxidative injury in some contexts. Its major clinical limitations are myelosuppression and cumulative dose–dependent cardiomyopathy, plus severe tissue injury if extravasated (leaks outside the vein). -Cumulative cardiomyopathy risk is real and dose-dependent; labels note higher risk at higher cumulative doses (often cited around >550 mg/m², with lower limits in higher-risk patients). -Mechanism split: tumor kill is primarily Topo II + DNA damage, while cardiotoxicity is strongly linked to TOP2β/mitochondrial pathways (redox/iron biology remains discussed, but not the only story). -Administration hazard: extravasation can cause severe local injury;
Time-Scale Flag (TSF): P / R / G
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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 |
| 256- | AL, | doxoR, | Allicin Overcomes Doxorubicin Resistance of Breast Cancer Cells by Targeting the Nrf2 Pathway |
| - | in-vitro, | BC, | MCF-7 | - | in-vitro, | BC, | MDA-MB-231 |
| 2586- | Api, | doxoR, | Apigenin sensitizes doxorubicin-resistant hepatocellular carcinoma BEL-7402/ADM cells to doxorubicin via inhibiting PI3K/Akt/Nrf2 pathway |
| - | in-vitro, | HCC, | Bel-7402 |
| 4991- | ART/DHA, | doxoR, | Dihydroartemisinin alleviates doxorubicin-induced cardiotoxicity and ferroptosis by activating Nrf2 and regulating autophagy |
| - | in-vivo, | Nor, | H9c2 |
| 1380- | BBR, | doxoR, | treatment with ROS scavenger N-acetylcysteine (NAC) and JNK inhibitor SP600125 could partially attenuate apoptosis and DNA damage triggered by DCZ0358. |
| - | in-vivo, | Nor, | NA |
| 2591- | CHr, | doxoR, | Chrysin enhances sensitivity of BEL-7402/ADM cells to doxorubicin by suppressing PI3K/Akt/Nrf2 and ERK/Nrf2 pathway |
| - | in-vitro, | HCC, | Bel-7402 |
| 4738- | Se, | doxoR, | Selenium Attenuates Doxorubicin-Induced Cardiotoxicity Through Nrf2-NLRP3 Pathway |
| - | NA, | Nor, | NA |
| 1495- | SFN, | doxoR, | Sulforaphane protection against the development of doxorubicin-induced chronic heart failure is associated with Nrf2 Upregulation |
| - | in-vivo, | Nor, | NA |
| 1494- | SFN, | doxoR, | Sulforaphane potentiates anticancer effects of doxorubicin and attenuates its cardiotoxicity in a breast cancer model |
| - | in-vivo, | BC, | NA | - | in-vitro, | BC, | MCF-7 | - | in-vitro, | Nor, | MCF10 |
| 2215- | SK, | doxoR, | Shikonin alleviates doxorubicin-induced cardiotoxicity via Mst1/Nrf2 pathway in mice |
| - | in-vivo, | Nor, | NA |
| 3405- | TQ, | doxoR, | Protective effect of thymoquinone against doxorubicin-induced cardiotoxicity and the underlying mechanism |
| - | vitro+vivo, | NA, | 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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