Glioblastoma, the most common type of glioma in adults, presents a grim prognosis with a median overall survival of only 13.5 months and a 5-year survival rate of a mere 5.8%. Glioblastoma is known for its resistance to many traditional cancer treatments, including chemotherapy and radiation therapy. Developing effective treatments for glioblastoma is challenging due to the complexity of the brain, the blood-brain barrier, and the highly invasive nature of the tumor. Temozolomide (TMZ) is an oral chemotherapy drug commonly used in the treatment of Glioblastoma. However, one of the significant challenges in Glioblastoma treatment is the development of resistance to temozolomide. Resistance to this chemotherapy agent can lead to treatment failure and disease progression. Addressing temozolomide resistance in GBM remains a significant clinical challenge. Researchers are actively exploring various strategies to overcome resistance, including the development of combination therapies, the use of targeted agents, and immunotherapy approaches. Hence, the quest for innovative therapeutic strategies is imperative. In this context, a recent study published in Journal of Medicinal Chemistry by Kaito Ohta, Hiromi Ii, Chiami Moyama, Shota Ando, Hisanori Nambu, Susumu Nakata, and led by Professor Naoto Kojima from Kyoto Pharmaceutical University (Present address of Prof. Kojima: Nagasaki International University) offers promising insights. Building upon prior research on annonaceous acetogenins as potential anticancer agents, the authors investigated the synthesis and therapeutic potential of a simplified analog, 2, in the treatment of glioblastoma.
The study’s motivation arises from the pressing need for novel therapeutic strategies in glioblastoma treatment. While prior efforts have explored the combination of phosphodiesterase inhibitors like MN-166 (Ibudilast) with TMZ, the new study explored a class of compounds called annonaceous acetogenins, which are polyketides found in Annona plants in tropical and subtropical regions. Specifically, the authors investigated the potential of a simplified analog, 2, to inhibit glioblastoma stem cells (GSCs) and enhance the efficacy of TMZ.
The synthesis of analog 2 is notable for its simplicity, consisting of only five steps compared to the cumbersome 23-step synthesis required for its precursor, JCI-20679. The key structural modification involves replacing the tetrahydrofuran (THF) moiety in JCI-20679 with triethylene glycol units. Several analogs with variable substitution groups and alkyl side chains were synthesized to investigate their inhibitory activities against GSCs. The authors’ results showed that while analogs 2a and 2h exhibit a reduced inhibitory effect on GSCs compared to JCI-20679, it remains promising, especially when considering its simpler synthesis. Moreover, it is worth noting that the inhibitory activity is significantly influenced by the length of the alkyl side chain, with n-nonyl and n-decyl analogs 2j-k showing potent inhibitory effects. One of the study’s notable findings is the synergistic effect observed when combining analog 2k with TMZ. Glioblastoma cells are known to be resistant to TMZ due to mechanisms like autophagy and ATP production via oxidative phosphorylation. However, the combination of 2k and TMZ demonstrated a synergistic effect, with 2k exhibiting superior efficacy at lower concentrations compared to JCI-20679. Overcoming resistance to temozolomide is critical to improving the prognosis and outcomes for GBM patients.
To understand the mechanism behind 2k’s inhibitory effects, the researchers investigated its impact on the activation of AMP-activated protein kinase (AMPK). AMPK plays a crucial role in cellular energy homeostasis and has been implicated in cancer growth inhibition. The results indicate that 2k activates AMPK in GSCs, leading to an increased AMP/ATP ratio, similar to the mechanism of JCI-20679. Notably, 2k exhibited a higher level of p-AMPK expression and AMP/ATP ratio compared to JCI-20679, suggesting its potential as a more efficient AMPK activator.
The authors further substantiate the therapeutic potential of 2k through in vivo experiments in xenograft mouse models. Administering 2k significantly improved the event-free survival rate of model mice and suppressed glioblastoma growth, as demonstrated by reduced luminescence signals. Moreover, 2k’s effectiveness extended beyond glioblastoma, as it also inhibited tumor growth in a mouse xenograft model of human colon cancer.
In conclusion, the study by Professor Naoto Kojima and colleagues sheds light on the potential of analog 2k as a promising antitumor agent, particularly in the context of glioblastoma treatment. Its simplified synthesis, enhanced AMPK activation, and synergistic effect with TMZ make it a strong candidate for further investigation and development. The study’s findings also underscore the importance of considering alternative approaches in cancer therapy, such as the inhibition of mitochondrial function. With the approval of darinaparsin as a therapeutic agent for peripheral T-cell lymphoma, there is growing interest in mitochondrial inhibitors as potential cancer treatments. The precise mechanisms through which these inhibitors selectively target cancer cells warrant further exploration. The new study represents a crucial initial step and continued research and clinical trials will be necessary to determine the therapeutic potential and safety profile in glioblastoma patients.
Ohta K, Ii H, Moyama C, Ando S, Nambu H, Nakata S, Kojima N. Thiophene Carboxamide Analogs with Long Alkyl Chains Comprising Ethylene Glycol Units Inhibit Glioblastoma Cell Proliferation by Activating AMPK. J Med Chem. 2023 ;66(9):6403-6413. doi: 10.1021/acs.jmedchem.3c00474.