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13-oxyingenol dodecanoate derivatives induce mitophagy and ferroptosis through targeting TMBIM6 as potential
Yaxu Wang1, Liwei Gu2, Jichong Li1
1Key Laboratory of Computational Chemistry Based Natural Antitumor Drug Research & Development, Liaoning Province, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China.
Abstract:
Ingenol diterpenoids continue to attract the attention for their extensive biological activity and novel structural features. To further explore this type of compound as anti-tumor agent, 13-oxyingenol dodecanoate (13-OD) was prepared by a standard chemical transformation from an Euphorbia kansui extract, and 29 derivatives were synthesized through parent 13-OD. Their inhibition activities against different types of cancer were screened and some derivatives showed superior anti-non-small cell lung cancer (NSCLC) cells cytotoxic potencies than oxaliplatin. In addition, TMBIM6 was identified as a crucial cellular target of 13-OD using ABPP target angling technique, and subsequently was verified by pull down, siRNA interference, BLI and CETSA assays. With modulating the function of TMBIM6 protein by 13-OD and its derivatives, Ca2+ release function was affected, causing mitochondrial Ca2+ overload, depolarisation of membrane potential. Remarkably, 13-OD, B6, A2, and A10-2 induced mitophagy and ferroptosis. In summary, our results reveal that 13-OD, B6, A2, and A10-2 holds great potential in developing anti-tumor agents for targeting TMBIM6.
Insights
New ingenol diterpenoid derivatives show potent anti-cancer activity, particularly against non-small cell lung cancer (NSCLC). These compounds target TMBIM6, inducing cell death pathways like mitophagy and ferroptosis for potential tumor treatment.
Area of Science:
- Medicinal Chemistry
- Molecular Pharmacology
- Cancer Biology
Background:
- Ingenol diterpenoids are recognized for their diverse biological activities and unique chemical structures.
- Exploring novel anti-tumor agents is crucial for advancing cancer therapy.
Purpose of the Study:
- To synthesize and evaluate 13-oxyingenol dodecanoate (13-OD) derivatives as potential anti-cancer agents.
- To identify the cellular targets and mechanisms of action for 13-OD and its derivatives.
Main Methods:
- Synthesis of 29 derivatives from 13-OD, derived from Euphorbia kansui.
- Screening of cytotoxic activities against various cancer cell lines, including non-small cell lung cancer (NSCLC).
- Identification of TMBIM6 as a target using activity-based protein profiling (ABPP) and subsequent validation through biochemical and cellular assays (pull down, siRNA, BLI, CETSA).
Main Results:
- Several derivatives exhibited superior cytotoxic potency against NSCLC cells compared to oxaliplatin.
- TMBIM6 was confirmed as a key cellular target of 13-OD.
- Modulation of TMBIM6 affected calcium (Ca2+) release, leading to mitochondrial Ca2+ overload and membrane potential depolarization.
- Specific compounds (13-OD, B6, A2, A10-2) induced mitophagy and ferroptosis.
Conclusions:
- 13-OD and its derivatives, particularly B6, A2, and A10-2, demonstrate significant potential as anti-tumor agents.
- Targeting TMBIM6 represents a promising therapeutic strategy for cancer treatment, especially NSCLC.
- The induction of mitophagy and ferroptosis are key mechanisms underlying the anti-cancer effects of these compounds.
