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Multifaceted Anticancer Activity of Flavanone/Chromanone Intermediates for Five-Membered Heterocyclic Derivatives:
Pawel Hikisz1, Angelika A Adamus-Grabicka2, Elzbieta Budzisz3
1Department of Oncobiology and Epigenetics, Institute of Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland.
Abstract:
This study explores the multifaceted anticancer mechanisms of flavanone analogues and spiropyrazoline condensed with flavanone ring against colorectal cancer (CRC) cell lines. Five-membered heteroaromatic scaffolds, in particular, have gained prominence in medicinal chemistry as they offer enhanced metabolic stability, solubility and bioavailability, crucial factors in developing effective drugs. Building upon previous findings, we investigated three lead derivatives (1, 3, and 5) with potent antiproliferative activity (IC50 < 35 μM). The compounds induced pronounced oxidative stress, evidenced by increased lipid peroxidation and reduced membrane fluidity, primarily within the hydrophobic layers of cell membranes. Preincubation with the antioxidant N-acetylcysteine (NAC) significantly attenuated these effects, confirming the pivotal role of reactive oxygen species (ROS) in their cytotoxicity. Mechanistic studies revealed that the derivatives triggered intrinsic apoptosis, characterized by the cleavage of PARP and the activation of caspase-9 and caspase-3. Furthermore, the compounds modulated key signaling pathways involved in cell survival and proliferation. Specifically, they inhibited the pro-oncogenic ERK1/2 MAPK pathway while inducing cell line-dependent alterations in p38 and JNK activity. Concurrently, all derivatives reduced the level of the transcription factor Nrf2, a master regulator of antioxidant defense and a mediator of chemoresistance in CRC. Collectively, these findings indicate that flavanone/chromanone derivatives exert their anticancer activity through a synergistic mechanism involving ROS generation, disruption of redox homeostasis, inhibition of Nrf2 signaling, and modulation of MAPK-dependent apoptotic pathways. These results highlight the therapeutic potential of flavanone-based compounds and their spiropyrazoline analogues as multifunctional anticancer agents targeting oxidative stress and survival signaling in colorectal cancer.
Insights
Flavanone derivatives show potent anticancer effects against colorectal cancer by inducing oxidative stress and apoptosis. These compounds target key survival pathways, offering potential for new CRC therapies.
Area of Science:
- Medicinal Chemistry
- Cancer Biology
- Pharmacology
Background:
- Heteroaromatic scaffolds are crucial in drug development due to improved stability and bioavailability.
- Colorectal cancer (CRC) remains a significant health challenge, necessitating novel therapeutic strategies.
- Flavanone analogues and spiropyrazoline derivatives have shown promise in preclinical studies.
Purpose of the Study:
- To investigate the anticancer mechanisms of novel flavanone/spiropyrazoline derivatives against colorectal cancer cell lines.
- To elucidate the role of oxidative stress and specific signaling pathways in the compounds' cytotoxicity.
- To evaluate the therapeutic potential of these derivatives as multifunctional anticancer agents.
Main Methods:
- Synthesis and evaluation of flavanone analogues and spiropyrazoline derivatives.
- Assessment of antiproliferative activity using IC50 values.
- Measurement of oxidative stress markers (lipid peroxidation, membrane fluidity) and reactive oxygen species (ROS) generation.
- Induction of apoptosis analysis (PARP cleavage, caspase activation).
- Investigation of signaling pathway modulation (MAPK pathways, Nrf2).
Main Results:
- Three lead derivatives exhibited potent antiproliferative activity (IC50 < 35 μM) against CRC cell lines.
- Compounds induced significant oxidative stress, confirmed by N-acetylcysteine (NAC) preincubation.
- Apoptosis was triggered via the intrinsic pathway, involving PARP cleavage and caspase-3/9 activation.
- Inhibition of ERK1/2 MAPK and modulation of p38/JNK pathways were observed.
- Nrf2 levels were reduced, impacting antioxidant defense and chemoresistance.
Conclusions:
- Flavanone/chromanone derivatives exert anticancer effects through a synergistic mechanism involving ROS generation and redox homeostasis disruption.
- Inhibition of Nrf2 signaling and modulation of MAPK pathways contribute to the observed cytotoxicity.
- These compounds demonstrate significant therapeutic potential for colorectal cancer treatment by targeting oxidative stress and survival pathways.
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