糖尿病治療藥物對惡性腫瘤的作用及影響

李倩，馬力文

北京大學第三醫院腫瘤化療與放射病科，北京1001910

高胰島素血癥和高血糖癥是確認的致癌風險因素，不僅因為降糖藥物會影響胰島素的濃度，同時，也因其會直接影響細胞的生長、增殖與代謝，從而可能對腫瘤發生的風險有不同的影響。本文結合現有的研究及報道，對不同降糖藥物的機制及其對惡性腫瘤的影響作一綜述。

1 胰島素增敏劑

1.1 二甲雙胍

二甲雙胍抗腫瘤的機制主要是通過直接作用于癌細胞和間接作用于胰島素以降低血糖水平而發揮作用[1]。

1.1.1 直接作用機制MTOR信號通路是促進癌癥發生、發展的重要通路。二甲雙胍能夠通過影響線粒體氧化磷酸化途徑，從而導致能量應激和腺苷三磷酸（adenosine triphosphate，ATP）合成減少[2]。ATP水平降低會激活單磷酸腺苷活化蛋白激酶（adenosine monophosphate‐activated protein kinase，AMPK），而AMPK的激活會抑制MTOR信號通路[3]。此外，二甲雙胍可能也會通過AMPK非依賴的方式，即通過降低胰島素和胰島素樣生長因子（insu‐lin‐like growth factor，ⅠGF）水平而抑制MTOR信號通路[4]。二甲雙胍還可以通過激活肝臟激酶B1‐單磷酸腺苷活化蛋白激酶（liver kinase B1‐AMPK，LKB1‐AMPK）途徑抑制腫瘤的生長[5]。通過激活細胞周期抑制因子如p53、p21、cyclinD1，抑制腫瘤增殖和誘導凋亡[6‐7]。通過降低活性氧類（reactive oxygen species，ROS）物質的產生、還原型輔酶Ⅰ（nicotinamide adenine dinucleotide，NADH）的利用而干擾線粒體氧化磷酸化[2]。通過抑制非折疊蛋白反應（unfolded protein response，UPR）誘導凋亡，通過干擾脂肪酸代謝刺激免疫系統產生CD8T細胞[1]。通過抑制缺氧誘導因子‐1（hypoxia inducible factor‐1，HⅠF‐1）和血管內皮生長因子（vascular en‐do‐thelial growth factor，VEGF）的表達，從而抑制癌細胞在低氧環境下的生長、血管生成和腫瘤轉移[8]，同時也會干擾P糖蛋白的多藥耐藥基因（multidrug resistance 1，MDR1）表達[2]。

1.1.2 間接作用機制主要的間接作用是通過抑制肝糖異生降低血糖水平，減少胃腸葡萄糖吸收和降低循環胰島素水平[6]。主要是以LKB1/AMPK依賴和（或）非依賴的方式抑制糖異生[9]。通過肝細胞的單磷酸腺苷（adenosine monophosphate，AMP）蓄積而減少胰高糖素依賴的葡萄糖分泌[10]。此外，二甲雙胍會通過減弱κ基因結合核因子（nu‐clear factor‐kappa‐gene binding，NF‐κB）的活性從而抑制炎性反應的發生[11]，并可通過破壞腫瘤干細胞的上皮間質轉化（epithelial mesenchymal transition，EMT）預防轉移進程和腫瘤侵襲[12]。

1.1.3 二甲雙胍對不同癌種的影響研究顯示，二甲雙胍可降低乳腺癌、胰腺癌、肝癌、結直腸癌、前列腺癌、肺癌、卵巢癌、腎癌及頭頸部癌的發生風險[13‐22]，詳見表1。回顧性隊列研究顯示，二甲雙胍并不能改善晚期胰腺癌患者的生存質量[23]，反而會增加男性患者結直腸癌的發生率[14]。然而，另一些研究認為，二甲雙胍與喉癌等其他腫瘤的發病風險無關[24‐25]。以上爭議的原因可能是因為研究中病例選擇的偏倚及病例數量的不足所造成的：二甲雙胍常被用于患病時間短，無禁忌證（禁忌證如存在年齡大，合并肝腎功能疾病等）的患者，而這些禁忌證本身也會影響到腫瘤的發生風險。

因此，截至目前，雖然尚無明確結論表明二甲雙胍能夠降低腫瘤風險，但至少可以肯定的是，二甲雙胍不會增加其風險，因此，二甲雙胍是一種安全用藥。

1.2 噻唑烷二酮類藥物

1.2.1 機制噻唑烷二酮類屬于過氧化物酶體增生物激活受體γ（peroxisome proliferator‐activated re‐ceptor gamma，PPARγ）激動劑。激活PPAR可降低胰島素抵抗和改善血糖控制。體內外研究顯示，噻唑烷二酮類化合物（thiazolidinedione，TZD）（尤其是曲格列酮和環格列酮）通過影響PPARγ途徑促進細胞周期捕獲和凋亡[26]。與此同時，還存在PPARγ非依賴的抗腫瘤作用機制：通過抑制B細胞淋巴瘤‐2基因（B‐cell lymphoma‐2，Bcl‐2）和 Bcl‐xL的抗凋亡活性，導致Caspase依賴的癌細胞凋亡[26]。TZD還可通過切除特異性蛋白1（specificity pro‐tein 1，Sp1）抑制癌細胞增殖、轉移，降解Sp1會使雄激素受體（androgen receptor，AR）、前列腺特異性抗原（prostate specific antigen，PSA）、雌激素受體（estrogen receptor，ER）、凋亡抑制基因survivin、表皮生長因子受體（epidermal growth factor receptor，EGFR）和細胞間黏附分子‐1（intercellular cell adhe‐sion molecule‐1，ⅠCAM‐1）和血管細胞黏附分子‐1（vascular cell adhesion molecule 1，VCAM‐1）減少[26]。

1.2.2 噻唑烷二酮類對不同癌種的影響有研究發現，TZD使用者可降低乳腺癌、肺癌、肝癌、卵巢癌、前列腺癌、結直腸癌、腎癌、胰腺癌和甲狀腺癌的發生風險[27‐32]，詳見表1。在甲狀腺癌和軟組織肉瘤中，聯合化療還會減少癌細胞的化療耐藥，增強抗腫瘤活性[33]。相反，也有報道顯示，TZD會增加膀胱癌[34]、惡性黑色素瘤及非霍奇金淋巴瘤[31]的癌癥發生風險。

2 胰島素促泌劑

磺脲類藥物通過關閉胰腺β細胞的鉀通道，一方面會導致空腹和餐后胰島素水平升高，進而促進腫瘤生長，而另一方面是關閉鉀通道本身就具有抗腫瘤效應[35]。有研究顯示，使用磺脲類藥物的糖尿病患者的患癌風險會明顯增加，可增加結腸癌和肝癌的發生風險[36‐37]。同時也有研究顯示，胰島素或磺脲類藥物會降低28%前列腺癌的發生風險[38]。另外有研究發現，格列苯脲對卵巢癌細胞的浸潤和轉移有抑制作用[35]，但該結論也存在爭議[39]。一項來自英國的回顧性隊列研究發現：磺脲類較二甲雙胍的致癌風險高36%，但也不能排除其中的偏倚因素：醫務人員更傾向于給偏瘦的患者開磺脲類藥物[40]。另有來自15項研究的薈萃分析顯示，二甲雙胍可降低11%的結直腸癌患病風險，而磺脲類和胰島素會分別增加11%與33%結直腸癌的患病風險，但是差異無統計學意義[16]。

3 胰島素及胰島素類似物

Dejgaard等[41]發現使用胰島素類似物雖然比使用胰島素的患癌風險低，但使用長效胰島素類似物（甘精胰島素或地特胰島素）仍然存在致癌風險[42]。Karlstad等[43]發現使用胰島素的糖尿病患者除了前列腺癌的患病風險降低外，肝癌、胰腺癌、腎癌、胃癌和呼吸系統惡性腫瘤的發生風險均明顯升高；甘精胰島素使用者結腸癌的患病風險降低，而乳腺癌的患病風險升高。體外研究中，甘精胰島素在乳腺癌細胞、人類子宮內膜癌和結直腸癌細胞中均發揮抗凋亡作用[44]。有研究顯示，甘精胰島素使用者胰腺癌和前列腺癌的患病風險會增加。另外一些研究顯示，甘精胰島素不會增加使用者的患癌風險[45‐46]。但以上研究存在隨訪時間短等局限性，結論并不十分可靠。有薈萃分析顯示，使用更高劑量的胰島素也沒有導致癌癥的發生率增高[47]。因此，對于未控的糖尿病，不應該因為顧慮患癌風險而延遲使用胰島素進行治療。

表1 不同降糖藥物對致癌風險的影響

4 基于腸促胰素的藥物（GLP- 1激動劑，DDP- 4-i）

腸促胰素來自于腸，攝食后的反射性分泌會使血糖升高之前刺激胰島素分泌。針對2型糖尿病患者腸促胰素活性缺乏的情況，人們研究出針對腸促胰素治療的藥物，根據其不同的作用機制分為胰升糖素樣肽 1（glucagon‐like peptide‐1，GLP‐1）受體激動劑和二肽基肽酶4（dipeptidyl‐peptidase 4 inhibitor，DPP‐4）抑制劑兩類藥物。

基于美國食品藥品監督管理局的分析數據報道的不良事件，GLP‐1受體激動劑艾塞那肽以及DPP‐4抑制藥物西他列汀已受到質疑[48]。這兩類藥物可能會增加惡性腫瘤的發生風險，尤其是增加甲狀腺癌和胰腺癌的發生風險。

GLP‐1激動劑治療會誘導嚙齒類動物甲狀腺C細胞的成癌性，但是在人類甲狀腺C細胞中并未發現類似效應，可能因為GLP‐1受體在嚙齒類動物和人類細胞中的濃度不同（在嚙齒類動物細胞中濃度高，在人類細胞中濃度低）[49]。Nauck等[50]發現GLP‐1激動劑治療不會導致糖尿病患者的甲狀腺髓樣癌。

二肽基肽酶‐4抑制劑（dipeptidyl peptidase‐4 inhibitor，DDP‐4‐i）會通過抑制 DDP‐4酶阻斷對GLP‐1的降解。有研究表明，GLP‐1激動劑或DDP‐4‐i可增加胰腺癌的發生風險[51]。但也有研究發現，利拉魯肽可通過抑制PⅠ3K/AKT途徑發揮對胰腺癌的抗腫瘤活性作用[52]。艾塞那肽可抑制小鼠前列腺癌細胞和結腸癌細胞的增殖，加速乳腺癌細胞的凋亡[53]。Gokhale等[54]研究發現 DDP‐4‐i使用者胰腺癌的發生風險低于磺脲類使用者，而與TZD使用者胰腺癌的發生風險類似。有研究顯示，西他列汀也會減少鼠類的腸癌發生風險[55]。在其他研究中未發現DDP‐4‐i的促腫瘤活性作用[56]。GLP‐1受體激動劑和DDP‐4‐i抑制劑還可潛在地增加急性胰腺炎的不良反應，這可能會增加約2倍患胰腺癌的風險[48]。然而，另外一項回顧性分析[57]以及一項融合了25個研究的薈萃分析[58]均無法證明胰腺癌與艾塞那肽的相關性。

所以，基于腸促胰素的治療風險和獲益仍然是一個有爭議的問題，由于疾病的演化及進展需要很長的時間[59]，故需要開展長期前瞻性研究設計來分析它們具體的預后（胰腺炎、胰腺癌、甲狀腺髓樣癌）[60]。目前研究的數據尚不足以證明基于腸促胰素的治療會增加癌癥的發生風險。

5 α-葡萄糖苷酶抑制劑

α‐葡萄糖苷酶抑制劑競爭性抑制位于小腸的各種α‐葡萄糖苷酶，使淀粉類分解為葡萄糖的速度減慢，從而減緩腸道內葡萄糖的吸收，降低餐后高血糖。有研究發現，α‐葡萄糖苷酶抑制劑使用者會降低胃癌、肺癌的發生風險，但會增加腎癌的發生風險[19,61‐62]。

6 小結

不同種類的降糖藥物在腫瘤的發生、發展過程中可以產生不同的影響，相關的研究尚存在爭論。主要原因為以上研究多為回顧性研究，存在入組偏倚及隨訪時間較短的缺陷。因此，需要大規模長期隨訪的前瞻性研究來進一步驗證各種降糖藥物在不同癌種中可能的作用及機制。

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