由於化療藥物的發展、癌細胞藥物的普遍應用及其功效，癌症患者的存活率已大幅提升。有效的抗癌藥物已被證實會引起心肌病。而人類心肌細胞的獲取途徑有限，導致人們對癌症治療期間或之後引起心臟毒性治療所進行的研究產生了不同的觀點。從基礎研究的角度，缺乏收縮生理特徵的心肌細胞係不被視為「真正的」心肌細胞。囓齒類動物具有與人類不同的獨特晝夜節律特徵，從動物組織培養取得的細胞訊號路徑可能與人類細胞的訊號路徑並不完全相似。研究真正的人類心肌細胞面臨一些挑戰，例如侵入性操作和由於其高度分化的性質而導致的有限的增殖潛力。人類誘導多能幹細胞發育成心肌細胞在本研究中通過細胞收縮能力評估及生理電訊號測試，證實可望增強在學術領域當作實驗平台的功效。化療藥物Doxorubicin (Dox)以拓樸異構酶II為靶點來阻止癌細胞增殖，但會導致劑量依賴性心肌病變。Valsartan/sacubitril (ARNI)在心臟衰竭治療中的臨床應用基於Sacubitril活性代謝物抑制腦啡肽酶的機制，從而促進鈉和水的排泄，減輕血管收縮，避免不適當的心臟重塑。先前的許多研究已經證實，Dox引起的心臟毒性是由於活性氧（ROS）產生過多，導致粒線體損傷，造成體內代謝異常引發一系列下游細胞凋亡事件。 動物實驗結果證實Dox會引起心臟收縮功能異常，口服ARNI比Valsartan明顯提高小鼠的心臟功能並能提高存活率。應用已經建立好的人類誘導多能幹細胞來源的心肌細胞（hiPSC-CMs）作為藥物篩選平台來驗證動物實驗結果並探索心臟衰竭治療藥物背後的機制發現，給予添加ARNI組別的細胞，顯著降低了Dox引起的心臟毒性並提高了心肌細胞的存活率。此機制涉及了心肌細胞內質網中的細胞色素P450酶CYP26家族，ARNI有助於消除細胞內的ROS、減少Dox引起的內質網氧化壓力，進而增加蛋白質合成率，並會刺激TNFAIP8的表達，從而阻止細胞凋亡途徑的活化。本研究證實了Dox產生的ROS最初會對內質網造成損害、抑制心肌細胞內TNFAIP8的表現並活化細胞凋亡路徑。 ARNI作為心臟衰竭的一線臨床治療藥物其背後的機制可能涉減輕Dox誘導的內質網氧化壓力。

The survival rate of individuals with cancer has been substantially enhanced due to developments in chemotherapy drugs, the universal application of cancer cell medicines, and their efficacy. Effective anticancer drugs have been proven to cause cardiomyopathy, and the limited access to human cardiomyocytes has resulted in a significant focus of research on the cardiac toxicity induced during or after cancer treatment, leading to differing perspectives on therapy. From a basic research perspective, cardiac myocyte cell lines without contractile physiological characteristics are not classified as authentic cardiomyocytes. Rodents have unique circadian characteristics distinct from humans, and the signaling pathways in primary cultures may not be entirely similar to those in human cells. Studying true human cardiomyocytes poses several challenges, such as invasive procedures and limited proliferation potential resulting from their highly differentiated nature. In this study, human induced pluripotent stem cells (hiPSCs) were differentiated into cardiomyocytes and were evaluated through their contraction ability and physiological electrical signal testing. It was confirmed that these cells could potentially enhance their effectiveness as an experimental platform in academic research. The chemotherapy drug doxorubicin (Dox) targets topoisomerase II to inhibit the proliferation of cancer cells, but it leads to dose-dependent cardiomyopathy. The clinical application of Valsartan/sacubitril (ARNI) in heart failure treatment is based on the mechanism by which the active metabolite of Sacubitril inhibits neprilysin, thereby promoting sodium and water excretion, reducing vasoconstriction, and preventing inappropriate cardiac remodeling. Numerous previous studies have confirmed that Dox-induced cardiotoxicity is due to the excessive production of reactive oxygen species (ROS), leading to mitochondrial damage, which triggers a series of downstream apoptotic events due to metabolic abnormalities in the body. Animal experiments confirmed that Dox-induces cardiac contractile dysfunction, and oral ARNI significantly improved heart function and survival rates in mice compared to Valsartan. Using cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) as a drug screening platform to validate the animal experiment results and explore the mechanisms behind heart failure treatments, it was found that the addition of ARNI significantly reduced Dox-induced cardiotoxicity and improved the survival rate of cardiomyocytes. This mechanism involves the cytochrome P450 enzyme CYP26 family in the endoplasmic reticulum, which helps eliminate intracellular ROS, reduces Dox-induced oxidative stress in the endoplasmic reticulum, increases protein synthesis rates, and stimulates the expression of TNFAIP8, thereby preventing the activation of apoptotic pathways. This study suggests that Dox-induced ROS initially causes damage to the endoplasmic reticulum, and ARNI, as a first-line clinical treatment for heart failure, may mitigate Dox-induced oxidative stress in the endoplasmic reticulum.

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