Teaching and Research Division, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, P. R. China.
Department of Chemistry, The University of Hong Kong, Hong Kong SAR, P. R. China.
Am J Chin Med. 2020;48(5):1179-1202. doi: 10.1142/S0192415X20500585.
Over-expression of calpains in tumor tissues can be associated with cancer progression. Thus, inhibition of calpain activity using specific inhibitors has become a novel approach to control tumor growth. In this study, the anticancer potential of cryptotanshinone in combination with calpain inhibitor had been investigated in colon cancer cells and tumor xenograft. Cryptotanshinone elicited an initial endoplasmic reticular (ER) stress response, whereas prolonged stress would result in the promotion of apoptosis. It was then discovered that cryptotanshinone could cause rapid and sustained increase in cytosolic calcium in colon cancer cells accompanied by early GRP78 overexpression, which could be attenuated by pre-treatment of the calcium chelator BAPTA-AM. Cryptotanshinone also facilitated an early increase in calpain activity, which could be blocked by BAPTA-AM or the calpain inhibitor PD150606. A dynamic interaction between GRP78 and calpain during the action of cryptotanshinone was unveiled. This together with the altered NF-[Formula: see text]B signaling could be abolished by calpain inhibitor. GRP78 knockdown increased the sensitivity of cancer cells to cryptotanshinone-evoked apoptosis and reduction of cancer cell colony formation. Such sensitization of drug action had been confirmed to be p53-dependent by using p53-mutated (HT-29) and p53-deficient (HCT116 p53) cells. The synergistic antitumor effect of cryptotanshinone and calpain inhibitor was further exhibited . Taken together, findings in this study exemplify a new chemotherapeutic regimen comprising cryptotanshinone and calpain inhibitor by regulation of calpain and calcium homeostasis. This has provided us with new insights in the search of a potential target-specific neoadjuvant therapy against colon cancer.
肿瘤组织中钙蛋白酶的过度表达与癌症的进展有关。因此，使用特异性抑制剂抑制钙蛋白酶的活性已成为控制肿瘤生长的一种新方法。在这项研究中，研究了隐丹参酮与钙蛋白酶抑制剂联合应用于结肠癌细胞和肿瘤异种移植的抗癌潜力。隐丹参酮引发了初始内质网（ER）应激反应，而持续的应激会促进细胞凋亡。随后发现，隐丹参酮可导致结肠癌细胞中细胞质钙的快速和持续增加，并伴有早期 GRP78 过表达，而用钙螯合剂 BAPTA-AM 预处理可减弱这种作用。隐丹参酮还促进钙蛋白酶活性的早期增加，用 BAPTA-AM 或钙蛋白酶抑制剂 PD150606 可阻断这种增加。隐丹参酮作用过程中揭示了 GRP78 和钙蛋白酶之间的动态相互作用。这种作用以及改变的 NF-[Formula: see text]B 信号转导可以被钙蛋白酶抑制剂所消除。GRP78 敲低增加了癌细胞对隐丹参酮诱导的细胞凋亡和癌细胞集落形成减少的敏感性。通过使用 p53 突变型（HT-29）和 p53 缺陷型（HCT116 p53）细胞，证实了这种药物作用的敏化是 p53 依赖性的。隐丹参酮和钙蛋白酶抑制剂的协同抗肿瘤作用进一步得到了展示。总之，本研究的结果说明了一种新的化疗方案，包括隐丹参酮和钙蛋白酶抑制剂，通过调节钙蛋白酶和钙稳态。这为我们寻找针对结肠癌的潜在靶向新辅助治疗提供了新的见解。
