6  癌症与衰老的关系

   根据癌症和年龄的关系可以确定癌症和衰老是同步的，所以他们之间一定有着紧密的联系。从细胞层面来理解，衰老的九大特征和癌症的特征也有一定联系。肿瘤细胞有十大特征：自给自足生长信号（Self-Sufficiency in Growth Signals）；抗生长信号的不敏感（Insensitivity to Antigrowth Signals）；抵抗细胞死亡(ResistingCell Death)；潜力无限的复制能力(Limitless Replicative Potential)；持续的血管生成(Sustained Angiogenesis)；组织浸润和转移(TissueInvasion and Metastasis)；避免免疫摧毁(Avoiding ImmuneDestruction)；促进肿瘤的炎症（Tumor Promotion Inflammation）；细胞能量异常（Deregulating Cellular Energetics）；基因组不稳定和突变（Genome Instability and Mutation）^[52]。我们把癌症的特征和衰老的特征放在表7中，试图找出他们的联系。

表7 癌症与衰老联系

   看得出来肿瘤细胞也是因为受到环境因素的影响而发生损伤，这与衰老的特征基本一致。逻辑上，让肿瘤细胞发生死亡有助于抗癌，这与我们的衰老模型又是一致的。

   如果抑制其抵抗细胞死亡，也就是诱导肿瘤细胞凋亡、自噬或坏死，很大程度抑制了癌症的发生。从逻辑上考虑，由于肿瘤细胞是非正常细胞，机体自身天生应该对其有抑制作用，也就是这些细胞应该自动发生凋亡，之所以不发生凋亡与其自身特征有关。研究发现，一些癌症或许不能完全归因为遗传损伤，而是衰老细胞绕过了告诉它们停止生长的开关所引起，衰老细胞与癌细胞之间的行为存在相似之处表明，如果衰老细胞设法逃脱死亡，它们有潜力变为癌症^[53]。甚至于，衰老的成纤维细胞通过释放致癌因子对临近细胞有致癌作用^[54]。新的观点认为，癌症和衰老的根源是一样的^[16]。如果肿瘤细胞属于衰老细胞，它理应走向死亡。因此我们认为，肿瘤细胞是因为具有的一些特殊能力让其不走向死亡，而长期滞留在机体内。和抗衰老的思路一致，诱导肿瘤细胞发生自噬、凋亡或坏死可以抗肿瘤。

   Nampt抑制剂APO866可以显著降低细胞内NAD+的水平，此过程可以诱导肿瘤细胞线粒体自噬，从而杀死多发骨髓瘤细胞，而外部补充NAM则会反转APO866介导的多发骨髓瘤细胞死亡^[55]。裸鼹鼠和盲鼹鼠不得癌症的重要原因是他们的凋亡和坏死程序能够及时启动。

   针对肿瘤细胞的两个特征也许是消灭肿瘤的最佳方式。该两个特征就是，抵抗细胞死亡和细胞能量异常。诱导衰老细胞死亡的思路同样适用于肿瘤细胞。尽管肿瘤细胞有自身的特征，一般癌症病人存在是由于肿瘤细胞不在机体环境作用下自动走向死亡，但是相对于正常的细胞，肿瘤细胞和衰老细胞一样本身发生了变化，也应该更怕氧化性强的物质，也更怕酸性环境。

   通过口服西地那非治疗3例患有囊状淋巴管瘤的儿童，通过用药，3位患儿的肿瘤体积均出现明显的缩小^[56]。西地那非是5-磷酸二酯酶抑制剂，磷酸二酯酶是NO-cGMP通路的负调节因子，因此西地那非能够通过释放生物活性物质一氧化氮。因此，我们认为一氧化氮这种自由基起到抑制肿瘤的直接作用。

   在针对乳腺和黑素瘤癌细胞的实验中发现，硝酸甘油通过产生一氧化氮可以加强一般化疗药物杀死癌细胞的作用^[57]。促一氧化氮释放的前体药物，诱导乳腺癌癌细胞死亡，同时保留正常乳腺上皮细胞^[58]。普遍认为，高浓度的一氧化氮合酶表达，可以对肿瘤细胞产生抑制其生长的毒性作用^[59]。过氧化氢可以诱导Hela细胞发生凋亡^[60]。

   可以看出，自由基或ROS能够诱导肿瘤细胞发生凋亡就如同他们诱导衰老细胞发生凋亡一样，我们估计二氧化氯同样可以诱导肿瘤细胞死亡。

   肿瘤细胞和衰老细胞一样，更多的是依靠低氧的糖酵解方式提供能量。早在80 多年前就发现肿瘤细胞的糖代谢较正常细胞旺盛，而且即使是在有氧条件下也依赖于糖酵解，该现象称为“Warburg效应”，其机制与肿瘤细胞的细胞膜上的葡萄糖转运蛋白(Glut) 功能活跃，且己糖激酶活性增强有关。“Warburg效应”的结果是细胞产生大量糖酵解产物——乳酸。从糖脱下来的大量H⁺不能像有氧氧化那样经过呼吸链氧化为水，大量的 H⁺聚集将使细胞内面临pH（pHi） 酸化和发生凋亡的威胁，而肿瘤细胞增强的泌酸功能使细胞内pHi 得以维持，但对周围正常的宿主细胞将产生不利影响。肿瘤细胞的“Warburg 效应”使肿瘤细胞比正常细胞产生更多的酸，但对肿瘤细胞pH检测发现细胞内pHi 值较正常细胞无明显区别，而细胞外pH(pHe) 和细胞内酸性囊泡内的pH(pHv) 明显低于正常细胞，提示可能与肿瘤细胞有较强的泌酸功能有关^[61]。

   为了躲避酸性微环境的毒性，肿瘤细胞遂向外排出氢离子，最终产生细胞外的酸性环境以及细胞内的碱性环境。肿瘤细胞通过上调细胞质膜的氢离子相关转运蛋白，如钠氢交换蛋白(Na⁺／H⁺)、Na⁺／K⁺-ATPase、囊泡型H⁺-ATPases、H⁺／Cl^-共输送体和单羧酸转运蛋白(MCT) 等，来实现这一机制^[62]。

   因此，我们猜想如果通过增加压力让肿瘤细胞泌酸功能降低，那就会引起肿瘤细胞内pHi降低，使其酸中毒，从而诱导肿瘤细胞凋亡或死亡。而增加压力，即使肿瘤细胞外环境的pH(pHe)降低，让肿瘤细胞的运输H⁺离子的质子泵增加压力，并最终崩溃。

   有较多的文献支持，酸性环境能够诱导肿瘤细胞发生凋亡。比如，酸性环境，通过p53介导诱导人腺癌和胃癌的细胞株凋亡^[63]。

   实验表明：给予体外培养的胃癌AGS细胞一个pH为6.0的酸性环境,这种酸性环境使细胞外H⁺离子浓度升高，可能通过抑制肿瘤细胞的NHE-1的Na⁺-H⁺交换功能使细胞内糖酵解产生的过多H⁺离子无法排出使本来偏碱性的细胞内环境明显酸化，这样既起到了改变胃癌细胞外环境的作用，同时也改变了细胞内环境。胃癌细胞的这种内外环境的酸化作用改变了适合它生长增殖的细胞内外环境的酸碱度，从而使大部分胃癌细胞停止增殖^[64]。

   Rich IN等证明了从白血病患者体内获得的白细胞系及外周淋巴血细胞有着比正常造血组织细胞普遍的、具有统计学意义的高的pH值。说明了在胞内pH值与正常造血细胞和白血病细胞的细胞周期调控之间存在一种直接的关系。利用这种关系，他们用Na⁺/H⁺交换体的抑制剂5-（N，N-hexamethylene）-amiloride（HMA）处理白血病细胞，降低了胞内pH值，从而诱导了细胞凋亡^[65]。

   可见，类似于对抗衰老细胞一样，酸性二氧化氯溶液既具有强的氧化性，又具有较强的酸性，我们预计酸性二氧化氯溶液有助于促进肿瘤细胞的凋亡。接下来我们即将开展这方面的实验。

7 二氧化氯诱导细胞死亡

   在研究二氧化氯消毒剂对人牙龈成纤维细胞（human gingival fibroblast）的影响的实验中发现，二氧化氯溶液对人牙龈成纤维细胞半数致死量LD₅₀为0.16 mmol/L，且以诱导细胞坏死而非凋亡为主^[66]。

   通过对培养基的年轻或衰老成纤维细胞的各类毒性压力反应的实验中发现，衰老的成纤维细胞经历更多的坏死，而不是像年轻细胞那样经历更多的p53依赖性凋亡^[67]。凋亡作为程序性死亡，可能更多依赖细胞内部健全的功能所介导，而要想使细胞更快速死亡，更多可能需要通过外部物质诱导坏死而达到。

结合以上分析，我们判断，酸性二氧化氯溶液可以更多的通过细胞坏死而使衰老细胞死亡，而对年轻的细胞影响不大。

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完整的论文发布在中国科技论文在线：我这样的原创论文，很难找到期刊发表，为了确立首发权，在科技论文在线公布。201401-1194 (1).pdf