Nazıroğlu Mustafa, Çiğ Bilal, Blum Walter, Vizler Csaba, Buhala Andrea, Marton Annamária, Katona Róbert, Jósvay Katalin, Schwaller Beat, Oláh Zoltán, Pecze László
Neuroscience Research Center, Suleyman Demirel University, Isparta, Turkey.
Department of Neuroscience, Health Science Institute, Suleyman Demirel University, Isparta, Turkey.
PLoS One. 2017 Jun 22;12(6):e0179950. doi: 10.1371/journal.pone.0179950. eCollection 2017.
There is convincing epidemiological and experimental evidence that capsaicin, a potent natural transient receptor potential cation channel vanilloid member 1 (TRPV1) agonist, has anticancer activity. However, capsaicin cannot be given systemically in large doses, because of its induction of acute pain and neurological inflammation. MRS1477, a dihydropyridine derivative acts as a positive allosteric modulator of TRPV1, if added together with capsaicin, but is ineffective, if given alone. Addition of MRS1477 evoked Ca2+ signals in MCF7 breast cancer cells, but not in primary breast epithelial cells. This indicates that MCF7 cells not only express functional TRPV1 channels, but also produce endogenous TRPV1 agonists. We investigated the effects of MRS1477 and capsaicin on cell viability, caspase-3 and -9 activities and reactive oxygen species production in MCF7 cells. The fraction of apoptotic cells was increased after 3 days incubation with capsaicin (10 μM) paralleled by increased reactive oxygen species production and caspase activity. These effects were even more pronounced, when cells were incubated with MRS1477 (2 μM) either alone or together with CAPS (10 μM). Capsazepine, a TRPV1 blocker, inhibited both the effect of capsaicin and MRS1477. Whole-cell patch clamp recordings revealed that capsaicin-evoked TRPV1-mediated current density levels were increased after 3 days incubation with MRS1477 (2 μM). However, the tumor growth in MCF7 tumor-bearing immunodeficient mice was not significantly decreased after treatment with MRS1477 (10 mg/ kg body weight, i.p., injection twice a week). In conclusion, in view of a putative in vivo treatment with MRS1477 or similar compounds further optimization is required.
有令人信服的流行病学和实验证据表明，辣椒素这种有效的天然瞬时受体电位阳离子通道香草酸受体1（TRPV1）激动剂具有抗癌活性。然而，由于辣椒素会引发急性疼痛和神经炎症，所以不能大剂量全身给药。MRS1477是一种二氢吡啶衍生物，若与辣椒素一起添加，它可作为TRPV1的正变构调节剂，但单独使用则无效。添加MRS1477可在MCF7乳腺癌细胞中诱发Ca2+信号，但在原代乳腺上皮细胞中则无此作用。这表明MCF7细胞不仅表达功能性TRPV1通道，还能产生内源性TRPV1激动剂。我们研究了MRS1477和辣椒素对MCF7细胞活力、半胱天冬酶-3和-9活性以及活性氧生成的影响。用辣椒素（10 μM）孵育3天后，凋亡细胞比例增加，同时活性氧生成和半胱天冬酶活性也增加。当细胞单独用MRS1477（2 μM）或与辣椒素（10 μM）一起孵育时，这些效应更为明显。TRPV1阻滞剂辣椒平可抑制辣椒素和MRS1477的作用。全细胞膜片钳记录显示，用MRS1477（2 μM）孵育3天后，辣椒素诱发的TRPV1介导的电流密度水平增加。然而，用MRS1477（10 mg/kg体重，腹腔注射，每周两次）治疗后，MCF7荷瘤免疫缺陷小鼠的肿瘤生长并未显著降低。总之，鉴于可能在体内使用MRS1477或类似化合物，还需要进一步优化。
