以調變電熱治療增強薑黃素與白藜蘆醇在結直腸癌小鼠動物模式的免疫活化能力及抗腫瘤效果

Abstract

調變電熱治療是一種腫瘤熱治療的方式，它可以透過促進熱休克蛋白的生成與釋放來活化宿主的免疫反應，引發腫瘤細胞的凋亡及壞死，同時達到破壞細胞膜完整性以增進腫瘤細胞對於化療藥的攝取。薑黃素與白藜蘆醇皆是具有抗氧化性的天然植物分子，也被證實能有效的抑制各種腫瘤的生成。然而，他們較差的生體可利用率使之在臨床治療上的效力受限，此研究嘗試以CT26結直腸癌細胞的體外與同種異體動物模式，評估調變電熱治療與薑黃素、白藜蘆醇合併使用時的抗癌能力及其機制。我們的研究結果顯示，此合併治療能夠顯著地造成CT26腫瘤細胞的凋亡、壞死及細胞週期停滯，而產生協同性的原因可能與mEHT能有效促進這兩種物質在細胞中的吸收濃度有關。小鼠活體實驗也證實此合併治療能促使CD3+T淋巴球及F4/80+巨噬細胞在腫瘤內的浸潤增加，且能有效抑制CT26癌細胞的生長。本篇的實驗結果顯示，透過mEHT本身的抗癌機制，並搭配薑黃素與白藜蘆醇本身所具有的抗氧化、提升免疫活性、抑制癌細胞生長的特點，並能更有效的達到對抗腫瘤之效果。

Modulated electro hyperthermia (mEHT) is one of the cancer hyperthermia treatments which has been demonstrated to activate host immunity by inducing the release of heat shock proteins, triggering apoptosis and necrosis, and destroying the integrity of cell membrane to enhance cellular uptake of chemo-drugs in tumor cells. Both curcumin and resveratrol are phytochemicals function as effective antioxidants and potential inhibitors for tumor developments; however, their poor bioavailability is regarded as a major obstacle for clinical cancer treatments. This study intends to investigate if mEHT could synergistically increase the anti-cancer efficacy of combined usage of curcumin and resveratrol in CT26 in vitro and in vivo models. The preliminary results showed that curcumin combined resveratrol could produce synergistic anti-tumor effect of CT26 cells by cell cycle arrest. The further experiment indicated co-treatment of mEHT with curcumin and resveratrol significantly induced cell apoptosis and cell necrosis of CT26 cells. This triple combined therapy also efficiently inhibited the growth of CT26 tumor by inducing recruiting CD3+ T cells and F4/80+ macrophages. The results shown here have suggested a naturally compound-based, non-toxic, but effective anti-tumor strategy for clinical cancer therapies. mEHT can create a favorable tumor microenvironment for an immunological chain reaction that improves the success of combined treatments of curcumin and resveratrol.