鐵依賴性細胞死亡 Ferroptosis
鐵依賴性細胞死亡 Ferroptosis
細胞凋亡的發生除了常見的程序性死亡,也可能因環境的改變所導致。科學家發現,當體內同時存在鐵質和氧氣時會誘導鐵依賴型細胞死亡(Ferroptosis)的發生。鐵依賴型細胞死亡會因為脂質超氧自由基 (Lipid reactive oxygen species, ROS) 在體內不停地堆積,而體內抗氧化不足以負荷的情況下,誘導代謝異常的發生 [1,2]。
體內的鐵離子主要以二價鐵和三價鐵兩個形態所組成。而運鐵蛋白在運送鐵離子的運送過程中,鐵質會不停地從二價轉為三價,此反應過程稱為芬頓反應 (Fenton reaction)[3,4]。芬頓反應中所釋放出的電子和離子誘導羥基自由基 (Hydroxyl radicals)。這些自由基會進一步的攻擊細胞膜上磷脂雙分子層的多元不飽和酰基鏈 (Polyunsaturated acyl chains),誘導更多的脂質自由基 (Lipid radicals)的生成。多重不穩定型自由基藉由質子(Proton)的釋放 ,不斷的攻擊細胞膜上的磷脂質(Propagation phase),產生更多不穩定型脂質過氧化物自由基 (Reactive lipid peroxyl radicals)進一步增加體內的氧化壓力 [7-9]。
反應過程
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穀胱甘肽 (Glutathione)是體內重要的抗氧化酵素,由三個氨基酸:cysteine, glutamate 和 glycine 所組成。其中又以半胱氨酸最為重要。當細胞質內半胱氨酸的濃度足夠時,可以維持體內氧化壓力的平衡,避免氧化壓力所帶來的傷害。而穀胱甘肽過氧化物酶4 (Glutathione hydroperoxidase 4, GPX4)是由還原型的 GSH和4個硒原子 (Selenium)鍵結組成。當體內穀胱甘肽濃度不足時,則使 GPX4 活性降低,無法將體內的超氧自由基 (ROS)清除,最終誘導鐵依賴性細胞死亡的發生 [9]。
在科研實驗中,可以透過抑制 xc--glutathione-GPX4 來模擬體內鐵依賴型細胞死亡的發生。而 Ferroptosis-inducing compounds (FINs) 可以被分為兩種:
Class I: 小分子穀胱甘肽抑制劑,如:Erastin等
Class II: 非穀胱甘肽消耗型抑制劑,如:(1S,3R)-RSL3, ML-162等
常見產品:
Ferroptosis Inducers (FINs)
Class I FINs
藉由限制 cystine 的攝取影響 GSH 的產生。
Item No. | Product Name |
31806 | CAY10773 |
17754 | Erastin |
27087 | Erastin2 |
27088 | Imidazole Ketone Erastin (IKE) |
15025 | Sulfasalazine |
Class II FINs
藉由抑制 GPX4 的活性,進而使脂質過氧化產生。
Item No. | Product Name |
30784 | JKE-1674 |
30786 | JKE-1716 |
20455 | ML-162 |
23282 | ML-210 |
32812 | PACMA 31 |
19288 | (1S,3R)-RSL3 |
Class III FIN
負向調控 GPX4 蛋白並且活化squalene synthase (SQS)。
Item No. | Product Name |
25180 | FIN56 |
Class IV FINs
這些過氧化物會藉由氧化鐵離子並且促進脂質 ROS 反應,引發 ferroptosis。
Item No. | Product Name |
11816 | Artemisinin |
11817 | Artesunate |
28788 | Chlorido[N,N'-disalicylidene-1,2-phenylenediamine] iron(III) |
25096 | FINO2 |
GSH Depleters & Redox Modulators
降低細胞外的 GSH 並且引發 ROS 反應。
Item No. | Product Name |
10024 | Acetaminophen |
14484 | L-Buthionine-(S,R)-Sulfoximine (BSO) |
16115 | N-Acetyl-4-benzoquinone imine (NAPQI) |
31769 | QD-394 |
FSP1 Inhibitor
FSP1 的抑制阻止 CoQ10 的還原反應,進而使其抗氧化的效果降低。
Item No. | Product Name |
29483 | iFSP1 |
Iron Oxidation
鐵藉由 transferrin receptor 進入細胞,提高鐵的攝取會使 ROS 與氧化型脂質的生成量提高。
Item No. | Product Name |
32030 | Transferrin (human, recombinant) |
32031 | Transferrin Receptor/CD71 Extracellular Domain (human, recombinant) |
32311 | Transferrin Receptor/CD71 Rabbit Monoclonal Antibody |
Fluorescent Iron Indicators
Item No. | Product Name |
25393 | Phen Green SK diacetate |
31095 | Rhodamine dithenoyl hydrazide |
Ferroptosis Inhibitors
Radical-Trapping Antioxidants
抗氧化物藉由停止 radical-driven propagation,防止磷脂質的過氧化反應。
Item No. | Product Name |
89910 | BHT |
11506 | Coenzyme Q10 |
17122 | Cu-ATSM |
70530 | Ebselen |
17729 | Ferrostatin-1 |
15475 | Idebenone |
17730 | Liproxstatin-1 |
31407 | RC363 |
31408 | RC574 |
25689 | SRS11-92 |
26752 | SRS16-86 |
81880 | tetrahydro-L-Biopterin (hydrochloride) |
25985 | (±)-α-Tocopherol |
10011659 | Trolox |
26525 | UAMC-3203 |
26819 | Vatiquinone |
MDM2/MDMX Inhibitors
藉由降低 FSP1 的表現來防止 MDM2/MDMX 複合物產生。
Item No. | Product Name |
18585 | (−)-Nutlin-3 |
27949 | NSC 207895 |
PPARα Activators
PPARα 的活化提高 FSP1 的表現量。
Item No. | Product Name |
10009145 | Bezafibrate |
18515 | Ciprofibrate |
10005368 | Fenofibrate |
10011211 | GW 9578 |
Iron Chelators
鐵離子的螯合可以去除過量的鐵離子,進而防止活化的羥基自由基產生。
Item No. | Product Name |
16021 | Ciclopirox |
30833 | CN128 |
33318 | CP21 |
16753 | Deferasirox |
20387 | Deferiprone |
14595 | Deferoxamine (mesylate) (DFO) |
20936 | Dp44mT |
ACSL4 Inhibitor
抑制 PUFA remodeling enzymes,可以防止膜上磷脂質的脂肪酸累積。
Item No. | Product Name |
32748 | PRGL493 |
15-LO Inhibitors
抑制細胞的脂肪加氧酶,可以防止膜上磷脂質的脂肪酸氧化。
Item No. | Product Name |
27391 | BLX3887 |
70300 | Nordihydroguaiaretic Acid |
10010518 | PD 146176 |
Lipoxygenases & Inhibitor Screening Assay
Item No. | Product Name |
60402 | 5-Lipoxygenase (human, recombinant) |
10341 | 12-Lipoxygenase (platelet-type, mouse recombinant) |
10011263 | 15-Lipoxygenase-2 (human, recombinant) |
760700 | Lipoxygenase Inhibitor Screening Assay Kit |
Identify Novel Inducers of Ferroptosis
GPX Detection
Item No. | Product Name |
703102 | Glutathione Peroxidase Assay Kit |
26906 | GPX4 (human, recombinant); selenocysteine incorporation confirmed by MS |
10005258 | GPX4 Polyclonal Antibody |
Glutathione (GSH) Assays & Derivatives
Item No. | Product Name |
703002 | Glutathione Assay Kit |
600360 | Glutathione Cell-Based Detection Kit (Blue Fluorescence) |
14953 | Glutathione ethyl ester |
10007461 | L-Glutathione, reduced |
GSH Redox/Detox Assays & Antibodies
Item No. | Product Name |
703202 | Glutathione Reductase Assay Kit |
703302 | Glutathione S-Transferase Assay Kit |
10010013 | Glutathione S-Transferase Polyclonal Antibody |
10197 | Glutathione S-Transferase Polyclonal FITC Antibody |
FSP1 Detection
Item No. | Product Name |
29611 | FSP1 (human, recombinant) |
29554 | Coumarin-Quinone Conjugate |
Lipid ROS Detection
Lipid ROS Assay Kits
Item No. | Product Name |
501140 | DHN-MA EIA Kit |
705002 | Lipid Hydroperoxide (LPO) Assay Kit |
601290 | ROS Detection Cell-Based Assay Kit (DHE) |
10009055 | TBARS Assay Kit |
Lipid ROS Probes
Item No. | Product Name |
27086 | C11 BODIPY 581/591 |
62237 | DPPP |
Lipid Peroxidation End Products
Item No. | Product Name |
10004413 | 4-hydroperoxy 2-Nonenal |
32100 | 4-hydroxy Nonenal |
10185 | 4-oxo-2-Nonenal |
10627 | 4-hydroxy Nonenal Glutathione (trifluoroacetate salt) |
32110 | 4-hydroxy Nonenal Mercapturic Acid |
Oxidized Phospholipids
Item No. | Product Name |
24383 | 1-Palmitoyl-2-(±)17(18)-EpETE-sn-glycero-3-PC |
62924 | PAz-PC |
10044 | PGPC |
25746 | PGPC-d6 |
10031 | POV-PC |
21138 | 1-Stearoyl-2-15(S)-HETE-sn-glycero-3-PC |
21139 | 1-Stearoyl-2-15(S)-HETE-sn-glycero-3-PE |
26531 | 1-Stearoyl-2-15(S)-HpETE-sn-glycero-3-PC |
25856 | 1-Stearoyl-2-15(S)-HpETE-sn-glycero-3-PE |
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Reference:
1. Cao, J.Y. and Dixon, S.J. Cell. Mol. Life Sci. 73(11-12), 2195-2209 (2016).
2. Stockwell, B.R., Friedmann Angeli, J.P., Bayir, H., et al. Cell 171(2), 273-285 (2017).
3. Andrews, N.C. and Schmidt, P.J. Annu. Rev. Physiol. 69(1), 69-85 (2007).
4. Kawabata, H. Free Radic. Biol. Med. (2018).
5. Shah, R., Shchepinov, M.S., and Pratt, D.A. ACS Cent. Sci. 4(3), 387-396 (2018).
7. Shintoku, R., Takigawa, Y., Yamada, K., et al. Cancer Sci. 108(11), 2187-2194 (2017).
8. Wenzel, S.E., Tyurina, Y.Y., Zhao, J., et al. Cell 171(3), 628-641 (2017).
9. Ingold, I., Berndt, C., Schmitt, S., et al. Cell 172(3), 409-422 (2018).
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