于義
【摘要】 糖尿病是一種常見(jiàn)的慢性疾病, 近年在全球的發(fā)病率以指數(shù)式上升, 嚴(yán)重威脅到人類(lèi)的生命。糖尿病本身致死率不高, 但會(huì)引發(fā)一系列危及生命的代謝綜合征。治療糖尿病的藥物很多, 主要機(jī)制是直接降低血糖、升高血液中胰島素濃度或者改善胰島素抵抗等。近年來(lái)很多研究發(fā)現(xiàn)糖尿病與腫瘤的發(fā)生有很高的相關(guān)性, 糖尿病治療藥物在一定程度上也會(huì)對(duì)腫瘤有直接或間接作用, 本文對(duì)糖尿病治療藥物與腫瘤的關(guān)系做簡(jiǎn)要介紹。
【關(guān)鍵詞】 糖尿病;腫瘤;糖尿病治療藥物
DOI:10.14163/j.cnki.11-5547/r.2020.11.085
Overview of the correlation between diabetes drugs and tumor? ?YU Yi. Chinese Academy of Medical Sciences, Institute of medicine of Peking Union Medical College, Beijing 100032, China
【Abstract】 Diabetes is a common chronic disease. Recently, the incidence is increasing exponentially, which threatens human life. Diabetes is fatal because of a series of life-threatening metabolic syndromes. There are many drugs for diabetes. The main mechanism is to lower blood glucose, increase insulin concentration in the blood, or improve insulin resistance. In recent years, many studies have found that diabetes has a high correlation with the occurrence of tumors. Diabetes drugs can also have a direct or indirect effect on tumors. This article briefly introduces the correlation between diabetes drugs and tumors.
【Key words】 Diabetes; Tumor; Diabetes drugs
糖尿病有兩種類(lèi)型, 1型糖尿病為胰島素依賴(lài)性糖尿病, 多見(jiàn)于青少年和兒童, 常由自身免疫性胰島β細(xì)胞損傷導(dǎo)致胰島素分泌絕對(duì)減少, 血糖升高;2型糖尿病為非胰島素依賴(lài)性糖尿病, 多發(fā)于>40歲人群, 特別是老年人, 表現(xiàn)為胰島素敏感性下降, 出現(xiàn)胰島素抵抗即胰島素分泌的相對(duì)不足。糖尿病可能伴隨一些腫瘤的發(fā)生, 2型糖尿病患者并發(fā)惡性腫瘤的幾率顯著高于非糖尿病患者[1], 尤其是乳腺癌、肝癌、胰腺癌、子宮內(nèi)膜癌等。糖尿病誘發(fā)癌癥可能涉及幾個(gè)方面:①高血糖直接或間接促進(jìn)腫瘤發(fā)生與轉(zhuǎn)移;②胰島素抵抗引起的高胰島素血癥促發(fā)腫瘤;③胰島素樣生長(zhǎng)因子(IGF)結(jié)合蛋白(IGFBP)表達(dá)減少導(dǎo)致IGF活性增強(qiáng), 促進(jìn)腫瘤發(fā)生;④糖尿病伴隨的全身組織炎癥反應(yīng)誘發(fā)腫瘤;⑤增強(qiáng)的氧化應(yīng)激促發(fā)腫瘤等[2]。除此之外, 糖尿病需要長(zhǎng)期藥物治療, 治療藥物對(duì)腫瘤發(fā)生發(fā)展也有很大的影響, 需要引起重視。
糖尿病治療的傳統(tǒng)口服藥物包括磺酰脲類(lèi)、雙胍類(lèi)、噻唑烷二酮(Thiazolidinediones, TZDs)類(lèi)和α-葡萄糖苷酶抑制劑;新型口服藥物有鈉-葡萄糖協(xié)同轉(zhuǎn)運(yùn)蛋白2(Sodium-glucose co-transporters2, SGLT2) 抑制劑和二肽基肽酶-4(Dipeptidyl peptide-4, DPP-4) 抑制劑;生物制劑除傳統(tǒng)的胰島素外, 新近還有胰高血糖素樣肽-1(Glucagon-like Peptide-1, GLP-1) 受體激動(dòng)劑。
1 胰島素
胰島素是由胰島β細(xì)胞合成的肽類(lèi)激素, 主要與胰島素受體(insulin receptor, IR) 、胰島素樣生長(zhǎng)因子1受體(Insulin-like growth factor 1 receptor, IGF-1R) 或者IGF-1R和IR雜交受體結(jié)合發(fā)揮作用。IR包括IR-A, IR-B兩種亞型, IR-B與胰島素結(jié)合引起促代謝的磷脂酰肌醇3-激酶/蛋白激酶B(Phosphatidylinositol 3-kinase/Protein kinase B, PI3K/PKB) 信號(hào)通路, 介導(dǎo)胰島素的降血糖作用, 與腫瘤發(fā)生無(wú)關(guān);IR-A, IGF-1R和IGF-1R, IR雜交受體與胰島素結(jié)合主要引起絲裂原活化蛋白激酶(mitogen-activated protein kinase, MAPK) 通路, 介導(dǎo)胰島素的促增殖作用, 能促進(jìn)腫瘤細(xì)胞的增殖[3-6]。多數(shù)腫瘤細(xì)胞過(guò)表達(dá)IR-A, 因此與普通細(xì)胞相比腫瘤細(xì)胞對(duì)高濃度的胰島素更加敏感, 對(duì)增殖的促進(jìn)作用也更強(qiáng)[7]。體內(nèi)胰島素缺乏會(huì)顯著降低癌細(xì)胞增殖速度, 減小腫瘤體積[8]。胰島素治療與乳腺癌、前列腺癌、胃癌、胰腺癌、結(jié)直腸癌、膀胱癌等腫瘤有關(guān)系, 但與每一種腫瘤的關(guān)系并不一致, 可能因?yàn)槟[瘤類(lèi)型或者應(yīng)用胰島素種類(lèi)的不同[9];胰島素類(lèi)似物是為了提高胰島素療效而對(duì)胰島素進(jìn)行修飾, 改變其結(jié)構(gòu)、作用特點(diǎn)和藥代動(dòng)力學(xué)的一類(lèi)藥物。對(duì)胰島素分子的修飾可能會(huì)使得這類(lèi)藥物對(duì)受體的選擇性和親和力改變從而改變下游信號(hào)通路, 對(duì)腫瘤的發(fā)生有不同作用。長(zhǎng)效胰島素類(lèi)似物甘精、地特胰島素在結(jié)直腸癌、乳腺癌和前列腺癌細(xì)胞中表現(xiàn)出較強(qiáng)的促增殖作用, 相比之下短效胰島素類(lèi)似物賴(lài)脯胰島素和門(mén)冬胰島素對(duì)增殖的促進(jìn)作用要弱一些[5]。除地特胰島素外胰島素類(lèi)似物處理的細(xì)胞處于G0/G1期顯著減少而G2/M期細(xì)胞上升, 說(shuō)明大多數(shù)胰島素類(lèi)似物能促進(jìn)細(xì)胞周期的進(jìn)行[5]。甘精胰島素對(duì)IGF-1R的親和力強(qiáng)于胰島素, 所以甘精胰島素對(duì)增值的促進(jìn)作用很強(qiáng), 而短效的門(mén)冬胰島素和賴(lài)脯胰島素的促增殖作用很弱[5]??偨Y(jié)以上研究, 胰島素類(lèi)似物對(duì)于腫瘤的促進(jìn)作用主要是與IR-A和IGF-1R結(jié)合實(shí)現(xiàn)的, 在新型胰島素類(lèi)似物的研究中, 應(yīng)該增加藥物與IR-B的親和力, 降低其與IR-A、IGF-1R的結(jié)合來(lái)避免對(duì)腫瘤發(fā)生、發(fā)展的促進(jìn)作用。
2 雙胍類(lèi)藥物
二甲雙胍是一種廣泛使用的口服降糖藥, 能提高機(jī)體對(duì)胰島素的敏感性, 促進(jìn)胰島素的作用從而降低血糖。二甲雙胍主要作用于線(xiàn)粒體, 能夠改變細(xì)胞能量代謝, 抑制線(xiàn)粒體氧化呼吸鏈, 使腺嘌呤核苷三磷酸(ATP)生成減少、腺苷一磷酸(AMP)增加, 活化AMP依賴(lài)的蛋白激酶(AMPK), AMPK是能量傳感器, 協(xié)調(diào)代謝和生長(zhǎng)的信號(hào)通路, 激活A(yù)MPK會(huì)促進(jìn)產(chǎn)生ATP的糖酵解途徑, 關(guān)閉需要消耗ATP的合成代謝通路, 抑制糖原形成[10]。二甲雙胍對(duì)腫瘤有抑制作用:抑制腫瘤細(xì)胞的增殖和遷移[11], 誘導(dǎo)AMPK活化, 抑制哺乳動(dòng)物雷帕霉素靶蛋白活化, 促進(jìn)p53, 干擾轉(zhuǎn)錄將癌細(xì)胞停留在G0/G1期從而減少癌細(xì)胞增殖, 抑制腫瘤細(xì)胞的蛋白質(zhì)合成從而抑制了腫瘤的發(fā)生、發(fā)展[11-13]。二甲雙胍抑制線(xiàn)粒體氧化呼吸鏈能降低內(nèi)源活性氧的產(chǎn)生, 降低體細(xì)胞的氧化壓力, 保護(hù)細(xì)胞DNA免受活性氧帶來(lái)的損傷, 減少了基因突變可能導(dǎo)致的腫瘤發(fā)生[14, 15]。二甲雙胍能降低血清胰島素水平, 其抗癌作用可能與改善胰島素抵抗相關(guān)[10]。二甲雙胍能選擇性作用于腫瘤干細(xì)胞發(fā)揮細(xì)胞毒性[16], 對(duì)結(jié)直腸癌細(xì)胞、前列腺癌細(xì)胞、卵巢癌細(xì)胞和乳腺癌細(xì)胞都有抑制作用[17]。苯乙雙胍是二甲雙胍的同類(lèi)物, 具有相似的作用機(jī)制。由于它有較強(qiáng)的脂溶性, 促進(jìn)其透過(guò)線(xiàn)粒體膜, 更有效地阻斷氧化呼吸鏈, 因而苯乙雙胍降糖作用比二甲雙胍強(qiáng)50倍[18]。但苯乙雙胍容易引起乳酸酸中毒, 這種危及生命的不良反應(yīng)迫使該藥物在許多國(guó)家禁用[19]。將苯乙雙胍與草氨酸鹽聯(lián)用時(shí), 后者作為乳酸脫氫酶抑制劑可以阻斷丙酮酸堆積轉(zhuǎn)化生成乳酸, 避免了乳酸酸中毒, 減少了苯乙雙胍的不良反應(yīng)[20]。很多腫瘤細(xì)胞的乳酸含量高于普通細(xì)胞, 高乳酸會(huì)促進(jìn)腫瘤細(xì)胞的增殖和遷移, 還能抑制免疫反應(yīng)的發(fā)生, 二者聯(lián)用降低了乳酸含量, 對(duì)腫瘤的增殖、遷移有抑制作用[20]。雙胍類(lèi)藥物能增加糖攝取, 加速糖酵解, 聯(lián)合草氨酸鹽時(shí)能大大降低ATP的產(chǎn)量, 可能是二者聯(lián)用殺傷腫瘤的一種機(jī)制[21]。
3 噻唑烷二酮類(lèi)藥物
常用的噻唑烷二酮類(lèi)藥物包括羅格列酮、吡格列酮、曲格列酮等。這類(lèi)藥物屬于過(guò)氧化物酶體增殖激活受體激動(dòng)劑, 是胰島素增敏劑, 能夠提高機(jī)體對(duì)胰島素的敏感性從而降低血糖。噻唑烷二酮類(lèi)藥物對(duì)脂肪細(xì)胞有雙重作用, 既能直接促進(jìn)脂肪組織吸收、存儲(chǔ)脂肪, 也能釋放脂聯(lián)素等脂肪因子調(diào)節(jié)胰島素抵抗[22]。很多腫瘤細(xì)胞都上調(diào)IGF-1受體介導(dǎo)的信號(hào)通路, 噻唑烷二酮類(lèi)藥物能阻斷IGF-1受體的作用, 抑制腫瘤細(xì)胞的增殖[22]。但是噻唑烷二酮類(lèi)藥物的抗癌作用在體內(nèi)外研究的結(jié)果有差異, 并且其抗癌效果與實(shí)驗(yàn)動(dòng)物種屬和癌癥類(lèi)型相關(guān), 在某些嚙齒動(dòng)物中的研究發(fā)現(xiàn)噻唑烷二酮類(lèi)藥物甚至有較強(qiáng)的促腫瘤作用[23]。羅格列酮對(duì)女性乳腺癌和生殖系統(tǒng)腫瘤沒(méi)有影響[24];吡格列酮能促進(jìn)膀胱癌的發(fā)生[25], 引起了藥物監(jiān)管部門(mén)的重視, 使得在一段時(shí)間內(nèi)有些國(guó)家禁止臨床使用吡格列酮。但吡格列酮能顯著降低乳腺癌的發(fā)病率, 與子宮癌的發(fā)生無(wú)關(guān)[26]。由于噻唑烷二酮類(lèi)藥物與腫瘤關(guān)系的復(fù)雜性, 使得在需要長(zhǎng)期應(yīng)用此類(lèi)藥物時(shí)應(yīng)謹(jǐn)慎[26]。
4 磺酰脲類(lèi)藥物
常用的磺酰脲類(lèi)藥物有甲苯磺丁脲、格列本脲、格列齊特等, 這類(lèi)藥物能促進(jìn)胰島素分泌, 降低血糖。胰島β細(xì)胞表面有磺酰脲類(lèi)藥物受體和與之偶聯(lián)的鉀通道, 藥物結(jié)合后阻止鉀離子外流, 使膜去極化, 增加電壓依賴(lài)鈣通道活性, 胞內(nèi)鈣離子濃度增高觸發(fā)胞吐作用釋放胰島素?;酋k孱?lèi)藥物對(duì)腫瘤的影響沒(méi)有一致定論[27]。糖尿病合并乳腺癌的患者使用磺酰脲類(lèi)降糖藥與二甲雙胍相比有更高的復(fù)發(fā)、轉(zhuǎn)移和病死率[28]??赡茉?yàn)榛酋k孱?lèi)降糖藥能促進(jìn)胰島素分泌但不能改善胰島素抵抗, 升高的胰島素與乳腺癌細(xì)胞表面過(guò)表達(dá)的A型胰島素受體和IGF-1受體結(jié)合促進(jìn)腫瘤的發(fā)生發(fā)展[28]。格列本脲是二代磺酰脲類(lèi)藥物, 能抑制多藥耐藥蛋白, 防止藥物外排, 從而提高對(duì)抗癌藥物的敏感性, 增加了抗腫瘤藥的藥效, 從而抑制腫瘤[29];鉀離子通道在腫瘤細(xì)胞中表達(dá)增加, 并對(duì)腫瘤的增殖有促進(jìn)作用, 格列本脲能抑制鉀通道開(kāi)放, 限制鉀離子外流促進(jìn)細(xì)胞膜去極化, 損傷腫瘤細(xì)胞并使其凋亡[29];格列本脲還能將細(xì)胞阻滯在G0/G1期, 通過(guò)抑制細(xì)胞生長(zhǎng)來(lái)發(fā)揮抗癌作用[29]。格列本脲抑制鉀通道會(huì)使線(xiàn)粒體中還原型煙酰胺腺嘌呤二核苷酸磷酸(NADPH)氧化酶催化生成的活性氧增加, 活性氧會(huì)降低線(xiàn)粒體膜電位, 活化氨基末端激酶, 從而抑制抗凋亡激酶活性, 促進(jìn)線(xiàn)粒體細(xì)胞色素C和凋亡誘導(dǎo)因子生成增加, 促進(jìn)腫瘤細(xì)胞凋亡[29];格列齊特對(duì)氧化應(yīng)激造成的DNA損傷有保護(hù)作用, 對(duì)細(xì)胞的核苷酸切除修復(fù)有促進(jìn)作用, 抑制基因突變[30];格列吡嗪還能通過(guò)抑制新生血管形成抑制腫瘤生長(zhǎng)和轉(zhuǎn)移[29]。
5 α-葡萄糖苷酶抑制劑
常用的α-葡萄糖苷酶抑制劑有阿卡波糖、伏格列波糖等。這類(lèi)藥物與α-葡萄糖苷酶競(jìng)爭(zhēng), 抑制寡糖分解為單糖, 減少小腸中糊精、淀粉、雙糖的吸收, 控制餐后血糖的升高。阿卡波糖能刺激L細(xì)胞, 增加GLP-1分泌從而發(fā)揮降血糖作用[31]。服用阿卡波糖的糖尿病患者患結(jié)直腸癌風(fēng)險(xiǎn)降低27%[32]。阿卡波糖競(jìng)爭(zhēng)各種糖苷酶導(dǎo)致的糖吸收不良的狀態(tài)降低了排泄物中膽汁酸和中性固醇類(lèi)的含量, 這兩種化合物在腸道中可能會(huì)轉(zhuǎn)化為致癌物引發(fā)結(jié)直腸癌, 所以阿卡波糖能抑制結(jié)直腸癌的發(fā)生[33]。阿卡波糖還能增加2型糖尿病患者腸道雙歧桿菌含量, 有助于減少腸道炎癥反應(yīng), 抑制消化道腫瘤[34]。但是另一項(xiàng)研究[35]卻沒(méi)有發(fā)現(xiàn)阿卡波糖的使用與消化道腫瘤之間的相關(guān)性。
6 SGLT2抑制劑
SGLT2抑制劑類(lèi)藥物主要包括卡格列凈、達(dá)格列凈、依帕列凈等。它們特異性抑制SGLT2[36], 阻斷葡萄糖轉(zhuǎn)運(yùn), 抑制葡萄糖在腎臟近端小管的重吸收, 促進(jìn)葡萄糖排泄從而降低血糖。由于SGLT2在很多腫瘤細(xì)胞中有表達(dá), 發(fā)現(xiàn)抑制SGLT2也能抑制腫瘤的發(fā)展[36]??ǜ窳袃裟芟抡{(diào)細(xì)胞周期蛋白依賴(lài)性激酶1、2, 抑制細(xì)胞周期的繼續(xù)[36];還能活化caspase3, 凋亡通路的酶促進(jìn)癌細(xì)胞的凋亡;卡格列凈還能抑制誘導(dǎo)血管生成因子白細(xì)胞介素-8(IL-8)、血管生成素等物質(zhì)的生成, 阻止腫瘤組織新生血管的形成[36];還能降低胞內(nèi)ATP的產(chǎn)生, 降低腫瘤細(xì)胞的增殖速率[36];有抗肝癌細(xì)胞增殖和抑制肝癌新生血管形成的作用[36];對(duì)胃癌有一定抑制作用[37]。卡格列凈、達(dá)格列凈、依帕列凈都不會(huì)促進(jìn)腫瘤的發(fā)生[37]。
7 胰高血糖素樣肽受體(GLP-1R)激動(dòng)劑
GLP-1是回腸、結(jié)腸的L細(xì)胞分泌的一種多肽, GLP-1能在餐后快速促進(jìn)胰島素分泌, 抑制胰高血糖素的分泌, 發(fā)揮血糖依賴(lài)性降血糖作用, 抑制胃排空, 降低食欲及食物攝取[38]。但是GLP-1很容易被DPP-4降解, 半衰期僅為2 min, 對(duì)其結(jié)構(gòu)進(jìn)行修飾得到的GLP-1受體激動(dòng)劑類(lèi)藥物半衰期明顯延長(zhǎng)[39], 這類(lèi)藥物作用強(qiáng)、不會(huì)引起低血糖反應(yīng), 但由于安全的不確定性尤其是與腫瘤和胰腺炎關(guān)系等問(wèn)題限制了這類(lèi)藥物的推廣[40]。隨著GLP-1受體激動(dòng)劑在臨床應(yīng)用的增加, 越來(lái)越多人關(guān)注這類(lèi)藥物對(duì)腫瘤的作用。常用的GLP-1受體激動(dòng)劑類(lèi)藥物包括艾塞那肽、杜拉魯肽等。艾塞那肽能抑制腫瘤的發(fā)生發(fā)展;作用于GLP-1受體, 上調(diào)腺苷-3', 5'-環(huán)化一磷酸(cAMP)和cAMP依賴(lài)蛋白激酶(PKA), 導(dǎo)致表皮生長(zhǎng)因子受體和信號(hào)轉(zhuǎn)導(dǎo)與轉(zhuǎn)錄激活因子3的失活, 最終導(dǎo)致包括原癌基因, 細(xì)胞周期蛋白依賴(lài)激酶1, B淋巴細(xì)胞瘤-2等多種基因的下調(diào)而發(fā)揮對(duì)腫瘤的抑制作用[41]。艾塞那肽通過(guò)與GLP-1受體結(jié)合抑制NF-κB信號(hào)通路抑制乳腺癌的發(fā)展[42];通過(guò)抑制MAPK信號(hào)通路抑制前列腺癌細(xì)胞的增殖[43]。但是GLP-1受體激動(dòng)劑有抗β細(xì)胞凋亡作用, 會(huì)促進(jìn)胰腺癌的發(fā)生發(fā)展[44], 嚙齒動(dòng)物中發(fā)現(xiàn)GLP-1受體激動(dòng)劑長(zhǎng)期作用于甲狀腺濾泡旁細(xì)胞能促進(jìn)鈣素分泌, 促進(jìn)濾泡旁細(xì)胞增殖, 進(jìn)而引發(fā)腫瘤[39]。
8 DPP-4抑制劑
DPP-4是一種非選擇性酶, 作用底物很多, 包括胃腸道激素、細(xì)胞因子和趨化因子等, DPP-4抑制劑能抑制體內(nèi)70%~90% DPP-4的活性[45], 抑制內(nèi)源GLP-1降解, 升高GLP-1濃度, 起到降血糖作用, 不存在惡心、體重增加、低血糖等不良反應(yīng)[40]。這類(lèi)藥物對(duì)腫瘤的作用仍在探索中。DPP-4抑制劑的應(yīng)用與胰腺癌、卵巢癌、神經(jīng)母細(xì)胞瘤等有關(guān), 在這些惡性腫瘤中, 低水平的DPP-4抑制劑能促進(jìn)腫瘤細(xì)胞的增殖和轉(zhuǎn)移[45], 其的免疫調(diào)節(jié)作用可能是其引起上述腫瘤發(fā)生的原因[46]。DPP-4抑制劑能降低乳腺癌的發(fā)病率[46]。根據(jù)目前的研究, 沒(méi)有足夠的證據(jù)說(shuō)明DPP-4抑制劑是否與腫瘤發(fā)病率增加相關(guān)。
9 討論
綜上所述, 胰島素能促進(jìn)腫瘤的發(fā)生發(fā)展。雙胍類(lèi)、α-葡萄糖苷酶抑制劑類(lèi)、SGLT-2抑制劑類(lèi)、GLP-1受體激動(dòng)劑和DPP-4受體抑制劑類(lèi)降糖藥一定程度上均能抑制腫瘤的增殖;而噻唑烷二酮類(lèi)和磺酰脲類(lèi)對(duì)腫瘤的作用不太明確。降糖藥與腫瘤的關(guān)系十分復(fù)雜, 各種藥物的抗癌效果還與劑量、應(yīng)用時(shí)間等因素密切相關(guān), 例如磺酰脲類(lèi)藥物能抑制腫瘤增殖, 但所需的濃度遠(yuǎn)高于降糖時(shí)濃度, 因此可能會(huì)帶來(lái)嚴(yán)重的不良反應(yīng)。對(duì)于糖尿病患者的藥物治療應(yīng)該綜合考慮到各種因素, 充分了解各類(lèi)藥物能帶來(lái)的各種反應(yīng), 這對(duì)于新藥開(kāi)發(fā)有指導(dǎo)意義, 增強(qiáng)降糖藥的治療作用, 降低不良反應(yīng), 開(kāi)發(fā)出療效好不良反應(yīng)小的糖尿病治療藥物。
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[收稿日期:2020-01-17]
作者單位:100032 中國(guó)醫(yī)學(xué)科學(xué)院&北京協(xié)和醫(yī)學(xué)院藥物研究所, 新藥作用機(jī)制研究與藥效評(píng)價(jià)北京市重點(diǎn)實(shí)驗(yàn)室