Cryptotanshinone-Induced p53-Dependent Sensitization of Colon Cancer Cells to Apoptotic Drive by Regulation of
Yue Wang1, Zhu Zhang1, Kathy Ka-Wai Auyeung2
1Teaching and Research Division, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, P. R. China.
Abstract:
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 in vivo. 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.
Insights
This study reveals cryptotanshinone and calpain inhibitors synergize to combat colon cancer by regulating calcium and calpain activity. This combination shows promise as a novel cancer therapy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Calpain over-expression is linked to cancer progression.
- Calpain inhibitors offer a novel strategy for tumor growth control.
- Cryptotanshinone's anticancer effects and interaction with calpains were investigated.
Purpose of the Study:
- To investigate the combined anticancer potential of cryptotanshinone and a calpain inhibitor in colon cancer.
- To elucidate the molecular mechanisms underlying their synergistic effects.
- To explore this combination as a potential neoadjuvant therapy for colon cancer.
Main Methods:
- Colon cancer cell lines and tumor xenografts were used.
- Endoplasmic reticulum (ER) stress, apoptosis, cytosolic calcium levels, GRP78, and calpain activity were measured.
- p53-dependent drug sensitization and in vivo antitumor effects were evaluated.
Main Results:
- Cryptotanshinone induced ER stress, apoptosis, and increased cytosolic calcium and calpain activity.
- GRP78 overexpression and altered NF-κB signaling were observed, modulated by calpain activity.
- Combined treatment showed synergistic antitumor effects in vitro and in vivo, dependent on p53 status.
Conclusions:
- Cryptotanshinone and calpain inhibitors exhibit synergistic anticancer effects in colon cancer.
- The combination regulates calpain and calcium homeostasis, offering a new therapeutic approach.
- This study provides insights for developing target-specific neoadjuvant therapies against colon cancer.
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