Human data in cancer 癌症中的人体数据
No clinical trials of MBZ as a cancer treatment have been completed to date. However, there are two well-documented case reports in the literature in favour of re-purposing MBZ as an anti-cancer therapy.
迄今为止，尚未完成 MBZ 作为癌症治疗的临床试验。然而，文献中有两个记录充分的病例报告支持将 MBZ 重新用作抗癌疗法。
In 2011, a case of long-term tumour control in metastatic adrenocortical cancer was published [23]. Adrenocortical cancer is a relatively rare malignancy with few treatment options in the case of non-resectable disease. The patient had experienced disease progression despite multiple chemotherapeutic protocols and several rounds of surgery. After all other treatment options had been exhausted, the patient discovered the pre-clinical evidence of MBZ action against adrenocortical cancer via Pubmed and forwarded the information to the clinicians, who agreed to use it based on this evidence and the relatively low toxicity of treatment. Monotherapy commenced with MBZ at a typical anti-helminthic dose of 100 mg twice a day. The patient experienced some regression in metastatic lesions, and overall the disease remained stable for 19 months of MBZ monotherapy, tolerating the treatment without side effects, and his quality of life returned to his baseline prior to his initial surgery. However, 24 months after the commencement of oral MBZ a scan showed disease progression, and everolimus was added to the MBZ but without additional benefit in disease control.
2011年，发表了转移性肾上腺皮质癌长期肿瘤控制的案例[ 23 ]。肾上腺皮质癌是一种相对罕见的恶性肿瘤，对于不可切除的疾病，治疗选择很少。尽管接受了多种化疗方案和几轮手术，该患者的疾病仍出现进展。在用尽所有其他治疗方案后，患者通过 Pubmed 发现了 MBZ 对抗肾上腺皮质癌的临床前证据，并将该信息转发给临床医生，临床医生基于该证据和相对较低的治疗毒性同意使用该信息。单药治疗开始时采用 MBZ，典型抗蠕虫剂量为 100 mg，每天两次。患者的转移病灶出现了一定程度的消退，在 MBZ 单药治疗 19 个月的时间里，总体疾病保持稳定，能够耐受治疗，没有副作用，生活质量恢复到初次手术前的基线。然而，开始口服 MBZ 24 个月后，扫描显示疾病进展，将依维莫司添加到 MBZ 中，但在疾病控制方面没有额外的益处。
A case of metastatic colon cancer treated with MBZ was described by Peter Nygren and Rolf Larsson in 2013 [24]. Here, a 74-year-old patient suffering from progressive metastatic colon cancer had been treated first with capecitabine, oxaliplatin, and bevacizumab, and then by capecitabine and irinotecan in the face of disease progression, and who had no standard treatment options available was started on an oral dose of MBZ of 100 mg twice a day. MBZ was selected based on the author’s previous pre-clinical work with MBZ [20]. After six weeks of monotherapy, radiological evaluation showed near complete remission of metastatic lesions in the lungs and lymph nodes and a good partial remission in the liver. However, the patient experienced elevated liver enzymes (AST and ALT), so MBZ was temporarily stopped and then started at half the dose, with the patient reporting no ill effects. Liver enzymes normalised and a subsequent round of CT scans confirmed the initial disease response. After ceasing treatment for approximately three months, the patient developed brain metastases that were treated with radiotherapy, following by evidence of disease in the lymph nodes. MBZ treatment was not recommenced following the discovery of the brain metastases or in subsequent disease progression. A further five patients have been treated, with one experiencing a minor remission [Private communication from Peter Nygren].
Peter Nygren 和 Rolf Larsson 在 2013 年描述了用 MBZ 治疗转移性结肠癌的病例 [ 24 ]。在此，一名患有进行性转移性结肠癌的 74 岁患者首先接受了卡培他滨、奥沙利铂和贝伐珠单抗治疗，然后在疾病进展时接受了卡培他滨和伊立替康治疗，并且没有可用的标准治疗方案。口服MBZ 100 mg，每天两次。 MBZ 的选择是基于作者之前对 MBZ 的临床前研究[ 20 ]。经过六周的单一治疗后，放射学评估显示肺部和淋巴结的转移病灶几乎完全缓解，肝脏也有良好的部分缓解。然而，患者出现肝酶（AST 和 ALT）升高，因此暂时停用 MBZ，然后以一半剂量开始服用，患者报告没有不良反应。肝酶恢复正常，随后一轮 CT 扫描证实了最初的疾病反应。停止治疗大约三个月后，患者出现脑转移，接受放射治疗，随后淋巴结出现疾病迹象。在发现脑转移或随后的疾病进展后，未重新开始 MBZ 治疗。另外五名患者已接受治疗，其中一名患者病情略有缓解。
Mechanism of action 作用机制
The anti-parasitic action of MBZ is due to its action as a microtubule-disrupting agent acting to prevent the polymerisation of tubulin in the gut of helminths, causing the parasites to die [25]. Tubulin is vital to cell division and is therefore a cancer target for several widely used chemotherapy drugs, including paclitaxel, colchicine, and vincristine. MBZ, as with the other benzimidazoles, binds to the colchicine-binding domain of tubulin [26].The inhibition of tubulin polymerisation by MBZ has been confirmed in vitro in a glioblastoma model [19] and in a melanoma model [17]. The latter work suggested that the apoptotic response to microtubule disruption is mediated by Bcl-2 phosphorylation. Subsequent work on melanoma confirmed this result, and also showed that MBZ decreased the levels of X-linked inhibitor of apoptosis (XIAP) [18], but to date this has not been confirmed in non-melanoma cell lines.
MBZ 的抗寄生虫作用是由于其作为微管破坏剂的作用，可防止蠕虫肠道中微管蛋白的聚合，从而导致寄生虫死亡 [ 25 ]。微管蛋白对于细胞分裂至关重要，因此是多种广泛使用的化疗药物（包括紫杉醇、秋水仙碱和长春新碱）的癌症靶标。 MBZ 与其他苯并咪唑一样，与微管蛋白的秋水仙碱结合域结合 [ 26 ]。MBZ 对微管蛋白聚合的抑制作用已在体外胶质母细胞瘤模型 [ 19 ] 和黑色素瘤模型 [ 17 ] 中得到证实。后一项工作表明，微管破坏引起的细胞凋亡反应是由 Bcl-2 磷酸化介导的。随后对黑色素瘤的研究证实了这一结果，并且还表明 MBZ 降低了 X 连锁凋亡抑制剂 (XIAP) 的水平 [ 18 ]，但迄今为止，这一点尚未在非黑色素瘤细胞系中得到证实。
While there are rare reports of reversible alopecia, urticaria, rash, gastro-intestinal upset, leukopenia, and neutropenia in some patients treated with high-dose MBZ, all adverse effects associated with other microtubule disruption agents, there do not appear to be any reports of peripheral neuropathy, which is commonly considered a classic adverse effect of microtubule disrupting agents, including the taxanes and the vinca alkaloids [27]. While this may suggest that the action of MBZ is independent of microtubule disruption, it may also be related to the fact that MBZ acts via the colchicine-binding domain, and that like colchicine, there is little effect in terms of neuropathic pain [28]. Of course, it is also possible that the anticancer activity of MBZ is mediated by additional molecular targets yet to be elucidated.
虽然在一些接受高剂量 MBZ 治疗的患者中，很少有关于可逆性脱发、荨麻疹、皮疹、胃肠道不适、白细胞减少和中性粒细胞减少的报告，但所有不良反应均与其他微管破坏剂相关，但似乎没有任何报告周围神经病变，这通常被认为是微管破坏剂（包括紫杉烷类和长春花生物碱）的典型副作用[ 27 ]。虽然这可能表明 MBZ 的作用与微管破坏无关，但也可能与 MBZ 通过秋水仙碱结合结构域发挥作用有关，并且与秋水仙碱一样，对神经性疼痛几乎没有影响 [ 28 ] 。当然，MBZ 的抗癌活性也可能是由其他尚未阐明的分子靶点介导的。
MBZ appears to be effective through p53-dependent and independent pathways. For example, in lung cancer cell lines, it was found that MBZ treatment caused post-translational p53 stabilization and the downstream expression of p21 and MDM2 [14]. In p53-null lung cancer cells exposure to MBZ caused cytochrome c accumulation, activation of caspase-9 and caspase-8, and cleavage of PARP and procaspase-3. This independence of p53 status is also evident in the analysis of melanoma cells, where wild-type and mutant p53 cell lines were sensitive to MBZ [17].
MBZ 似乎通过 p53 依赖性和独立途径发挥作用。例如，在肺癌细胞系中，发现MBZ处理导致翻译后p53稳定以及p21和MDM2的下游表达[ 14 ]。在 p53 缺失的肺癌细胞中，暴露于 MBZ 会导致细胞色素 c 积累、caspase-9 和 caspase-8 激活以及 PARP 和 procaspase-3 裂解。 p53 状态的这种独立性在黑色素瘤细胞的分析中也很明显，其中野生型和突变型 p53 细胞系对 MBZ 敏感 [ 17 ]。
There has been conflicting evidence regarding the effect that MBZ has on tumour neo-vascularisation, with some reports finding evidence that it has an anti-angiogenic effect and others finding none.
关于 MBZ 对肿瘤新生血管形成的影响存在相互矛盾的证据，一些报告发现证据表明它具有抗血管生成作用，而另一些报告则没有发现任何证据。
In the earliest work on the anti-cancer activity of MBZ, Mukhopadhyay and colleagues reported an anti-angiogenic effect on human lung cancer xenograft models [14]. However, in vivo analysis of adrenocortical cancer models failed to detect any anti-angiogenic activity compared to controls [16]. Some support for an anti-angiogenic action comes from an in silico study, which indicated that MBZ inhibits the action of VEGFR-2 by binding to it, a finding validated in vitro using a human umbilical vein endothelial cell (HUVEC) based angiogenesis functional assay [29]. Of note, the related drug albendazole has shown anti-angiogenic properties in an ovarian cancer model and in drug-resistant cell lines [30, 31], suggesting that an anti-angiogenic action may be common across a number of benzimidazoles.
在关于 MBZ 抗癌活性的最早研究中，Mukhopadhyay 及其同事报道了对人类肺癌异种移植模型的抗血管生成作用 [ 14 ]。然而，与对照相比，肾上腺皮质癌模型的体内分析未能检测到任何抗血管生成活性[ 16 ]。对抗血管生成作用的一些支持来自一项计算机模拟研究，该研究表明 MBZ 通过与 VEGFR-2 结合来抑制 VEGFR-2 的作用，这一发现在体外使用基于人脐静脉内皮细胞 (HUVEC) 的血管生成功能测定进行了验证[ 29 ]。值得注意的是，相关药物阿苯达唑在卵巢癌模型和耐药细胞系中显示出抗血管生成特性[ 30 , 31 ]，这表明抗血管生成作用可能在许多苯并咪唑类药物中普遍存在。
To date, the effect of MBZ or other benzimidazole on the immune response in cancer has not been investigated, though there is some evidence that albendazole synergised to stimulate the cellular immune response in mice treated for alveolar echinococcosis with the immunotherapeutic agent liposomal muramyl tripeptide phosphatidylethanolamine (L-MTP-PE) used in the treatment of osteosarcoma [32]. There is also increasing evidence that existing microtubule disrupting agents used at low or metronomic doses, including the taxanes and vinca alkaloids, exert a positive immunomodulatory action that may help to reverse the immunosuppressive effect of cancer [33–36]. We can speculate, mechanistically, that some of this immunomodulatory action is related to microtubule dynamics. Therefore, there may be a similar effect with MBZ and other benzimidazoles, and this may also be a factor in the anti-cancer effects of these drugs.
迄今为止，MBZ 或其他苯并咪唑对癌症免疫反应的影响尚未得到研究，尽管有一些证据表明阿苯达唑可协同刺激用免疫治疗剂脂质体胞壁酰三肽磷脂酰乙醇胺治疗肺泡包虫病的小鼠的细胞免疫反应。 L-MTP-PE）用于治疗骨肉瘤[ 32 ]。还有越来越多的证据表明，以低剂量或节拍剂量使用的现有微管破坏剂（包括紫杉烷类和长春花生物碱）可发挥积极的免疫调节作用，可能有助于逆转癌症的免疫抑制作用[ 33-36 ]。我们可以从机制上推测，这种免疫调节作用的一部分与微管动力学有关。因此，MBZ和其他苯并咪唑类药物可能有类似的作用，这也可能是这些药物具有抗癌作用的一个因素。