Recycling the Purpose of Old Drugs to Treat Ovarian Cancer
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The main challenge in ovarian cancer treatment is the management of recurrences. Facing this scenario, therapy selection is based on multiple factors to define the best treatment sequence. Target therapies, such as bevacizumab and polymerase (PARP) inhibitors, improved patient survival. However, despite their achievements, ovarian cancer survival remains poor; these therapeutic options are highly costly and can be associated with potential side effects. Recently, it has been shown that the combination of repurposed, conventional, chemotherapeutic drugs could be an alternative, presenting good patient outcomes with few side effects and low costs for healthcare institutions. The main aim of this review is to strengthen the importance of repurposed drugs as therapeutic alternatives, and to propose an in vitro model to assess the therapeutic value. Herein, we compiled the current knowledge on the most promising non-oncological drugs for ovarian cancer treatment, focusing on statins, metformin, bisphosphonates, ivermectin, itraconazole, and ritonavir. We discuss the primary drug use, anticancer mechanisms, and applicability in ovarian cancer. Finally, we propose the use of these therapies to perform drug efficacy tests in ovarian cancer ex vivo cultures. This personalized testing approach could be crucial to validate the existing evidences supporting the use of repurposed drugs for ovarian cancer treatment.Keywords:
Drug repositioning
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Metformin is an oral hypoglycemic agent that is commonly used in the treatment of type 2 diabetes mellitus. While metformin-associated metabolic acidosis is a widely recognized side effect of this drug, metformin-induced hepatotoxicity has been rarely reported in the literature. We present herein the case of a 52-year-old male in whom metformin-associated lactic acidosis and metformin-induced hepatotoxicity developed.
Lactic acidosis
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As a safe and effective antidiabetic drug , metformin has been considered to be the first line drug for the therapy of diabetes. With further research on metformin, it turns out that metformin can not only lower blood glucose but also display certain benefits for patients with polycystic ovary syndrome and nonalcoholic fatty liver disease, which is independent of the hypoglycemic effect of metformin. Furthermore, metformin can block cancer cells growth by activation of AMP-activated protein kinase and inhibition of mammalian target of rapamycin signaling pathway. In recent years, the effects of metformin on anti-atherosclerosis, endothelial function protection and other cardiovascular benefits have also become a research hotspot.
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有 bevacizumab 的治疗，一个 antiangiogenic 代理人，在病人与变形或 unresectable colorectal 癌症不到 4 年以前在日本被同意。Bevacizumab 与变形 colorectal 癌症改进病人的幸存；然而，它可以导致象流血那样的复杂并发症，它有时是致命的。因为治疗的潜在的风险超过它的好处， Bevacizumab 应该仅仅在小心的考虑以后被管理。因此，药品的公司不与大脑转移为病人推荐 bevacizumab 治疗。当一些报告支持 bevacizumab 的小心的使用时，其它报导与转移在病人禁止它的使用到中央神经系统(CNS ) 不总是是必要的，包括大脑。因此，在有大脑转移的 colorectal 癌症病人的 bevacizumab 治疗是争论的，并且大脑转移是否在反脉管的 endothelial 生长期间是为 intracranial 出血的一个风险因素，是不清楚的因素(VEGF ) 治疗。没有大脑转移，我们与周期性的 colorectal 癌症报导一个 65 岁的人和一个 65 岁的人；分别地，这些病人在 bevacizumab 的管理以后开发了 multifocal 和独居的 intracranial 出血。我们的调查结果建议就算病人没在 bevacizumab 治疗以前有大脑转移并且也建议大脑转移不是为有 bevacizumab 治疗的 intracranial 出血的一个风险因素，那 intracranial 出血能发生。这些调查结果也询问在 anti-VEGF 上从临床的试用与大脑转移排除病人的必要性治疗。
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To evaluate evidence from the medical literature that metformin is effective in preventing type 2 diabetes.Primary literature was accessed via a MEDLINE search (1966-December 2003) using the terms metformin, type 2 diabetes, and prevention.Two studies evaluated metformin's potential to prevent type 2 diabetes, finding that metformin maintained or reduced fasting blood glucose in non-diabetics. Recently, a large study by the Diabetes Prevention Program showed that metformin may reduce the incidence of diabetes. Researchers compared lifestyle changes, metformin therapy, and placebo groups. They found that both lifestyle changes (58%) and metformin therapy (31%) significantly reduced the occurrence of type 2 diabetes versus placebo.These studies provide evidence that metformin may reduce the occurrence of type 2 diabetes. Because long-term efficacy has not been determined, further studies are needed.
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症例 1：75 歳，女性。左肺癌術後再発，多発骨転移に対して docetaxel，bevacizumab 併用化学療法が開始された。投与 2 カ月後に食欲低下，発熱性好中球減少症を認め一旦休薬となった。3 カ月間休薬し，再投与 2 カ月後に右足首に潰瘍が出現したため当科へ紹介され受診した。当科受診時 bevacizumab は休薬されており，保存的治療で右足背の潰瘍は縮小傾向を認めていたが，その後 bevacizumab の投与が再開され急速に既存の潰瘍が拡大した。症例 2：62 歳，女性。再発乳癌，骨，肝転移に対して paclitaxel，bevacizumab 併用化学療法が開始された。投与 3 カ月後に右足背に潰瘍が出現し当科へ紹介され受診した。2 症例とも血液検査，画像検査で特に有意な所見は認められなかった。病理組織学的に表皮壊死，好中球を含む炎症細胞浸潤，毛細血管の増生とフィブリノイド変性，出血像を認めた。検査結果，臨床経過から bevacizumab による潰瘍と診断した。2 症例とも bevacizumab の投与を中止し，保存的潰瘍治療を行った。症例 1 では潰瘍はほとんど改善がみられず，全身状態が徐々に悪化し，再々投与 3 カ月後に原病死した。症例 2 は bevacizumab の投与中止後 8 カ月経過した時点で良好な肉芽組織の増生を認めている。 皮膚潰瘍を診察した際には，bevacizumab によるものも念頭に置き，投与中止など適切に対応する必要がある。
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Metformin is the most widely prescribed drug to treat patients with type II diabetes, for whom retrospective studies suggest that metformin may have anticancer properties. However, in experiments performed with isolated cells, authors have reported both pro- and anti-apoptotic effects of metformin. The exact molecular mechanism of action of metformin remains partly unknown despite its use for over 60 years and more than 17,000 articles in PubMed. Among the various widely recognized or recently proposed targets, it has been reported consistently that metformin is capable of inhibiting mitochondrial respiratory chain Complex I. Since most of the effects of metformin have been replicated by other inhibitors of Complex I, it has been suggested that the mechanism of action of metformin involved the inhibition of Complex I. However, compared to conventional Complex I inhibitors, the metformin-induced inhibition of Complex I has unique characteristics. Among these, the most original one is that the concentrations of metformin required to inhibit Complex I are lower in intact cells than in isolated mitochondria. Experiments with isolated cells, mitochondria or Complex I were generally performed using millimolar concentrations of metformin, while plasma levels remain in the micromolar range in both human and animal studies, highlighting that metformin concentration is an important issue. In order to explain the effects in animals based on observations in cells and mitochondria, some authors proposed a direct effect of the drug on Complex I involving an accumulation of metformin inside the mitochondria while others proposed an indirect effect (the drug no longer having to diffuse into the mitochondria). This brief review attempts to: gather arguments for and against each hypothesis concerning the mechanism by which metformin inhibits Complex I and to highlight remaining questions about the toxicity mechanism of metformin for certain cancer cells.
Mechanism of Action
Mitochondrial respiratory chain
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목적: Metformin은 암 발생 위험 및 사망률을 낮추는 효과가 있다. 당뇨를 동반한 4기 대장암 환자에서 metformin의 효과는 알려져 있지 않으며, 이번 연구는 당뇨를 동반한 4기 대장암 환자에서 항암약물요법 반응 및 생존율에 대한 metformin의 효과를 후향적으로 알아보고자 하였다. 대상 및 방법: 당뇨를 동반한 4기 대장암으로 진단된 106명의 환자 중 완화항암약물치료를 받은 81명의 환자와 근치적 수술을 시행한 25명의 환자를 대상으로 후향적 연구를 하였다. 각 군에서 metformin 사용여부에 따라 대상 환자의 임상적 특징 및 종양반응, 생존율 등을 조사하여 비교하였다. 결과: 완화항암약물요법을 시행한 환자군에서 metformin 복용군과 비복용군으로 나누어 단변량 및 다변량 분석을 시행한 결과, 항암약물요법 후 첫 번째 반응평가, 표적 병변의 크기 변화율, 무진행 생존율, 전체 생존율은 차이가 없었다. 근치적수술 환자군에서 무병 생존율은 metformin 복용군이 비복용군에 비하여 높았고(p=0.012), 다변량 분석에서도 암 재발률이 유의하게 적었다(HR, 0.024; 95% CI 0.001-0.435; p=0.010). 그러나 전체 생존율에서는 차이가 없었다. 결론: 당뇨를 동반한 4기 대장직장암 환자에서 근치적 수술 후 metformin을 복용하는 것은 암 재발률을 감소시키는 효과를 나타냈다.
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Surgical oncology
Refractory (planetary science)
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