Ibrahim-Hashim Arig, Wojtkowiak Jonathan W, de Lourdes Coelho Ribeiro Maria, Estrella Veronica, Bailey Kate M, Cornnell Heather H, Gatenby Robert A, Gillies Robert J
Department of Imaging, H. Lee Moffitt Cancer Center Tampa, FL 33612.
J Cancer Sci Ther. 2011 Nov 19;Suppl 1(4).
Malignant tumor cells typically metabolize glucose anaerobically to lactic acid even under normal oxygen tension, a phenomenon called aerobic glycolysis or the Warburg effect. This results in increased acid production and the acidification of the extracellular microenvironment in solid tumors. H ions tend to flow along concentration gradients into peritumoral normal tissue causing extracellular matrix degradation and increased tumor cell motility thus promoting invasion and metastasis. We have shown that reducing this acidity with sodium bicarbonate buffer decreases the metastatic fitness of circulating tumor cells in prostate cancer and other cancer models. Mathematical models of the tumor-host dynamics predicted that buffers with a pka around 7 will be more effective in reducing intra- and peri-tumoral acidosis and, thus, and possibly more effective in inhibiting tumor metastasis than sodium bicarbonate which has a pKa around 6. Here we test this prediction the efficacy of free base lysine; a non-bicarbonate/non-volatile buffer with a higher pKa (~10), on prostate tumor metastases model.
Oxygen consumption and acid production rate of PC3M prostate cancer cells and normal prostate cells were determined using the Seahorse Extracellular Flux (XF-96) analyzer. effect of 200 mM lysine started four days prior to inoculation on inhibition of metastasis was examined in PC3M-LUC-C6 prostate cancer model using SCID mice. Metastases were followed by bioluminescence imaging.
PC3M prostate cancer cells are highly acidic in comparison to a normal prostate cell line indicating that reduction of intra- and perit-tumoral acidosis should inhibit metastases formation. administration of 200 mM free base lysine increased survival and reduced metastasis.
PC3M prostate cancer cells are highly glycolytic and produce large amounts of acid when compared to normal prostate cells. Administration of non-volatile buffer decreased growth of metastases and improved survival indicating acidity plays a significant role in growth and invasion in-vivo.
恶性肿瘤细胞即使在正常氧张力下通常也通过无氧代谢将葡萄糖转化为乳酸，这种现象称为有氧糖酵解或瓦伯格效应。这导致实体瘤中酸产生增加和细胞外微环境酸化。氢离子倾向于沿浓度梯度流入肿瘤周围正常组织，导致细胞外基质降解和肿瘤细胞运动性增加，从而促进侵袭和转移。我们已经表明，用碳酸氢钠缓冲液降低这种酸度可降低前列腺癌和其他癌症模型中循环肿瘤细胞的转移适应性。肿瘤-宿主动力学的数学模型预测，pKa约为7的缓冲液在降低肿瘤内和肿瘤周围酸中毒方面将更有效，因此，可能比pKa约为6的碳酸氢钠在抑制肿瘤转移方面更有效。在这里，我们在前列腺肿瘤转移模型中测试这一预测——游离碱赖氨酸（一种pKa较高（约10）的非碳酸氢盐/非挥发性缓冲液）的功效。
使用海马细胞外通量（XF-96）分析仪测定PC3M前列腺癌细胞和正常前列腺细胞的耗氧率和产酸率。在使用SCID小鼠的PC3M-LUC-C6前列腺癌模型中，研究接种前四天开始使用200 mM赖氨酸对转移的抑制作用。通过生物发光成像追踪转移情况。
与正常前列腺细胞系相比，PC3M前列腺癌细胞酸性很强，这表明降低肿瘤内和肿瘤周围酸中毒应能抑制转移形成。给予200 mM游离碱赖氨酸可提高生存率并减少转移。
与正常前列腺细胞相比，PC3M前列腺癌细胞具有高度糖酵解能力并产生大量酸。给予非挥发性缓冲液可减少转移灶生长并提高生存率，表明酸度在体内生长和侵袭中起重要作用。
