Background
Oxaliplatin is a cytotoxic chemotherapy drug used to treat cancer. Oxaliplatin works by interfering with the development of DNA in a cell. This helps to treat cancer which is caused by cells rapidly growing and dividing out of control.
Oxaliplatin can induce DNA damage in cancer cells. Besides,oxaliplatin can interfere with the cell cycle, promote apoptosis, and induce autophagy in tumor cells[2,3]. Oxaliplatin inhibited cell viability, migration, and cloning formation of OSCC cells and induced cell death in vitro[1]. Oxaliplatin inhibited the growth of HCCLM3 and Hep3B cells.Downregulation of the anti-apoptotic proteins Bcl-2 and Bcl-xL and upregulation of the pro-apoptotic protein Bax during oxaliplatin-induced apoptosis[6]. Oxaliplatin was found to be active against C32 and G361 cell lines with IC50 values of 49.48 and 9.07 uM (1 h exposure), 9.47 and 1.30 uM (4 h exposure), and 0.98 and 0.14 uM (24 h exposure), respectively. At a 24 h exposure oxaliplatin appears to be significantly more active than cisplatin against the G361 cell line[4]. 85-88% of all platinum from oxaliplatin was bound to plasma proteins within the first 5 h with an average half-life of 1.71 +/- 0.06 h. When oxaliplatin was incubated in whole blood, the erythrocytes took up 37.1 +/- 2.1% of the total platinum in 2 h (maximum uptake) which was not exchangeable into plasma[5].
The in vivo anticancer effect of oxaliplatin was studied using a nude mouse subcutaneously implanted with CAL27 cells. The average volume of tumors was markedly smaller in the oxaliplatin group than in the control group. Therefore, these results indicated that oxaliplatin inhibited the growth of xenograft OSCC cells in vivo, which was accompanied by the upregulated expression of PARP1[1]. Oxaliplatin-treated mice displayed reduced weight gain, mechanical allodynia, and exploratory behavior deficits that were not significantly improved by exercise[7]. When investigated oxaliplatin-induced haematological toxicities and splenomegaly in mice, Blood analysis showed dose dependent decreases in white and red blood cell counts, and significant changes in haematological indices.Spleen weight was significantly increased indicating splenomegaly, and red pulp tissue exhibited substantial dysplasia[8]. Oxaliplatin-treated mice displayed reduced weight gain and behavioral deficits. Mice treated over a shorter course had significantly increased STAT3 phosphorylation in gastrocnemius muscles. Mice receiving extended oxaliplatin treatment demonstrated reduced hindlimb muscle mass with upregulation of myopathy-associated genes Foxo3, MAFbx, and Bnip3[9].
参考文献:
[1]. Li D, Kou Y, et,al. Oxaliplatin induces the PARP1-mediated parthanatos in oral squamous cell carcinoma by increasing production of ROS. Aging (Albany NY). 2021 Jan 20;13(3):4242-4257. doi: 10.18632/aging.202386. Epub 2021 Jan 20. PMID: 33495407; PMCID: PMC7906208.
[2]. Wang X, Li M, et,al. On-Demand Autophagy Cascade Amplification Nanoparticles Precisely Enhanced Oxaliplatin-Induced Cancer Immunotherapy. Adv Mater. 2020 Aug;32(32):e2002160. doi: 10.1002/adma.202002160. Epub 2020 Jun 28. PMID: 32596861.
[3]. Yan S, Zhou N, et,al. PFKFB3 Inhibition Attenuates Oxaliplatin-Induced Autophagy and Enhances Its Cytotoxicity in Colon Cancer Cells. Int J Mol Sci. 2019 Oct 30;20(21):5415. doi: 10.3390/ijms20215415. PMID: 31671668; PMCID: PMC6862230.
[4]. Mohammed MQ, Retsas S. Oxaliplatin is active in vitro against human melanoma cell lines: comparison with cisplatin and carboplatin. Anticancer Drugs. 2000 Nov;11(10):859-63. doi: 10.1097/00001813-200011000-00010. PMID: 11142694.
[5]. Pendyala L, Creaven PJ. In vitro cytotoxicity, protein binding, red blood cell partitioning, and biotransformation of oxaliplatin. Cancer Res. 1993 Dec 15;53(24):5970-6. PMID: 8261411.
[6]. Wang Z, Zhou J, et,al. Oxaliplatin induces apoptosis in hepatocellular carcinoma cells and inhibits tumor growth. Expert Opin Investig Drugs. 2009 Nov;18(11):1595-604. doi: 10.1517/13543780903292626. PMID: 19780708.
[7]. Lees JG, Abdulla M, et,al. Effect of exercise on neuromuscular toxicity in oxaliplatin-treated mice. Muscle Nerve. 2021 Aug;64(2):225-234. doi: 10.1002/mus.27329. Epub 2021 Jun 12. PMID: 34036599.
[8]. Lees JG, White D, et,al. Oxaliplatin-induced haematological toxicity and splenomegaly in mice. PLoS One. 2020 Sep 2;15(9):e0238164. doi: 10.1371/journal.pone.0238164. PMID: 32877416; PMCID: PMC7467301.
[9]. Feather CE, Lees JG, et,al. Oxaliplatin induces muscle loss and muscle-specific molecular changes in Mice. Muscle Nerve. 2018 Apr;57(4):650-658. doi: 10.1002/mus.25966. Epub 2017 Oct 6. PMID: 28881481.
奥沙利铂是一种用于治疗癌症的细胞毒性化疗药物。奥沙利铂通过干扰细胞中 DNA 的发育起作用。这有助于治疗由细胞快速生长和分裂失控引起的癌症。
奥沙利铂可诱导癌细胞中的 DNA 损伤。此外，奥沙利铂可干扰肿瘤细胞的细胞周期，促进细胞凋亡，诱导肿瘤细胞自噬[2,3]。奥沙利铂抑制 OSCC 细胞的细胞活力、迁移和克隆形成，并在体外诱导细胞死亡[1]。奥沙利铂抑制HCCLM3和Hep3B细胞的生长。在奥沙利铂诱导的细胞凋亡过程中，抗凋亡蛋白Bcl-2和Bcl-xL下调，促凋亡蛋白Bax上调[6]。发现奥沙利铂对 C32 和 G361 细胞系具有活性，IC50 值分别为 49.48 和 9.07 uM（暴露 1 小时）、9.47 和 1.30 uM（暴露 4 小时）以及 0.98 和 0.14 uM（暴露 24 小时）。暴露 24 小时后，奥沙利铂对 G361 细胞系[4] 的活性似乎明显高于顺铂。来自奥沙利铂的所有铂的 85-88% 在前 5 小时内与血浆蛋白结合，平均半衰期为 1.71 +/- 0.06 小时。当奥沙利铂在全血中孵育时，红细胞在2小时内占铂总量的37.1.+/- 2.1%（最大摄取量），不能交换入血浆[5]。
使用皮下植入 CAL27 细胞的裸鼠研究了奥沙利铂的体内抗癌作用。奥沙利铂组的平均肿瘤体积明显小于对照组。因此，这些结果表明奥沙利铂在体内抑制了异种移植OSCC细胞的生长，同时伴随着PARP1[1]的表达上调。奥沙利铂治疗的小鼠表现出体重增加减少、机械性异常性疼痛和探索行为缺陷，而运动并未显着改善这些缺陷[7]。当研究奥沙利铂引起的小鼠血液学毒性和脾肿大时，血液分析显示白细胞和红细胞计数呈剂量依赖性下降，血液学指标发生显着变化。脾脏重量显着增加表明脾肿大，红髓组织显着发育不良[8 ].奥沙利铂处理的小鼠显示出体重增加减少和行为缺陷。经过较短疗程治疗的小鼠腓肠肌中的 STAT3 磷酸化显着增加。接受奥沙利铂延长治疗的小鼠表现出后肢肌肉量减少，肌病相关基因 Foxo3、MAFbx 和 Bnip3[9] 上调。
Protocol
| Cell experiment [1]: |
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Cell lines
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OSCC cells
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Preparation Method
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In order to determine the effect of oxaliplatin on cell viability, CAL27 cells and SCC25 cells were treated with different concentrations of oxaliplatin for 12, 24, and 48 hours.
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Reaction Conditions
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0-300uM Oxaliplatin for 12, 24, and 48 hours
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Applications
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Oxaliplatin inhibited cell viability, migration, and cloning formation of OSCC cells and induced cell death in vitro.
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| Animal experiment [2]: |
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Animal models
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BALB/c mice
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Preparation Method
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Subjects were injected intraperitoneally (once every two days) with oxaliplatin (5 mg/kg in PBS, oxaliplatin group) or same volume of PBS (control group). After 21 days, mice were euthanized, and their xenografts were harvested and weighed.
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Dosage form
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5 mg/kg oxaliplatin for 21 days
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Applications
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Oxaliplatin inhibited tumor growth of OSCC and caused upregulation of PARP1 in vivo.
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参考文献:
[1]. Li D, Kou Y, et,al. Oxaliplatin induces the PARP1-mediated parthanatos in oral squamous cell carcinoma by increasing production of ROS. Aging (Albany NY). 2021 Jan 20;13(3):4242-4257. doi: 10.18632/aging.202386. Epub 2021 Jan 20. PMID: 33495407; PMCID: PMC7906208.
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