Investigating the potential of therapeutic candidates and their mechanism of action against lung and breast cancer

Abstract

Solid tumors are a major global public health challenge, characterized by limited treatment options, poor prognosis, and high mortality rates. According to WHO GLOBOCAN 2022 data, lung cancer has an incidence of 12.4% and a mortality rate of 18.7%, while breast cancer ranks second with an incidence of 11.6% and a mortality rate of 6.9%. Current treatments for lung and breast cancers include surgery, radiation, and chemotherapy. Despite chemotherapy being a key treatment, it is associated with drug resistance and non-specific toxicity. Due to a lack of targeted therapies, patients continue to receive drugs like docetaxel, doxorubicin, and cisplatin, which have severe side effects, highlighting the urgent need for advanced therapeutic strategies. Tumor hypoxia drives progression, metastasis, and drug resistance by stabilizing HIF-1α, which activates pathways involved in angiogenesis, apoptosis, and epithelial-to-mesenchymal transition (EMT). Zeb1, a hypoxia-induced transcription factor, promotes angiogenesis and metastasis by upregulating VEGF. Targeting Zeb1 may disrupt pro-angiogenic and immunosuppressive roles of macrophages within the tumor microenvironment (TME), offering a promising approach for cancer therapy. In this study, firstly, we synthesized fifteen novel imidazo[1,2-a] pyridine (IMPA) derivatives by hybridizing imidazo[1,2-a] pyridine with 2-amino-4H-pyran, aiming to develop potent anti-cancer agents. Among them five derivatives (IMPA-2, -5, -6, -8, and -12) showed significant cytotoxicity against lung cancer cells, promoting apoptosis and cell cycle arrest by upregulating p53-mediated genes and enhancing NOX activity. Secondly, rapid proliferation of cancer cells in solid tumors creates a hypoxic microenvironment, promoting aggressiveness and resistance to conventional chemotherapies. To mitigate this, oxygen delivery at the tumor site is done by developing of highly efficient lipid-shelled ONBs (L-ONBs) that significantly reduced lung and breast cancer aggressiveness by destabilizing hypoxia-inducible factor 1α (HIF-1α), thereby inhibiting cancer cell invasion and migration. Lastly, we developed highly efficient, less toxic cationic lipid-based nanoparticles (LNPs) using DOTAP and DCChol for delivering Zeb1siRNA to target tumor angiogenesis and also revealing Zeb1’s role in converting tumor macrophage into endothelial like cell phenotypes the observed plasticity of TAMs suggests that targeting Zeb1 may also disrupt the pro-angiogenic and immunosuppressive roles of macrophages within the TME, offering a multifaceted approach to cancer therapy. Overall, our findings suggest that novel IMPA derivatives, L-ONBs, and LNP conjugated Zeb1siRNA hold promise as innovative therapeutic candidates/strategies for treating NSCLC, TNBC, and other solid tumors, by addressing key challenges such as chemoresistance and hypoxia.