The Characterization of Molecular Pathways Mediated by Anticancerous Compounds in Cancer Models

Abstract

Cancer is a lethal heterogeneous disease that is one of the leading causes of mortality across the globe. Cancer is characterized by dysregulated cellular growth resulting in the mass proliferation of abnormal cells, ultimately leading to tumor formation. Breast cancer is a broad set of illnesses with numerous morphological traits, a wide range of appearances, and varying outcomes and responses to different treatments. Even though many recognized factors affect the incidence and development of breast cancer, it is still necessary to identify the novel molecular markers and cellular mechanisms that contribute to its progression. Researchers could improve methods for breast cancer diagnosis and therapy by better grasping the unique elements involved in breast carcinogenesis. Leukemia is a hematological malignancy characterized by the overproduction of immature white blood cells known as leucoblasts. These blast cells arise in blood and bone marrow, and infiltrate other body organs, such as the liver, spleen, lymph nodes, etc. Consequently, the normal hematopoietic process is halted, and malignant leukemic cells start to replace normal cells resulting in low production of red blood cells and platelets accompanied by an increase in white blood cells. Risk factors in leukemia progression are inherited or acquired via genetic mutations, chromosomal disorders, environmental factors such as exposure to ionizing radiations, carcinogens (benzene, alkylating agents) or previous therapies that pose an enhanced risk of leukemia. This study aimed to discover different markers involved in the prognosis of breast cancer and to find a better natural or synthetic compound for the chemotherapy of leukemia. Our first study investigated the prognostic significance of PKMYT1's gene in breast cancer. It was found that overexpression of PKMYT1 aids in cell proliferation and is xvi Abstract linked to poor survival of patients according to METABRIC, TCGA and Nottingham cohort. Our second study showed that the natural compound cinnamon and the chemotherapeutic drug doxorubicin could act as a better antileukemic agents. Their combination helps to overcome doxorubicin’s toxicity and can modulate apoptosis via the TRAIL route in a leukemic rat model. The increased expression of TRAIL pathway markers is potentially responsible for the synergy in the pro-apoptotic action of cinnamon when combined with doxorubicin. Our third study proposed a novel synthetic anti-cancer compound Zinc diethyldithiocarbamate (ZDTC) for leukemia treatment. Our findings showed that its combination with doxorubicin worked against leukemia and brought STMN1 gene expression back to normal. In addition, the combination modulated the effect via the Rel-A downregulation in the NF-κB pathway and DR5 upregulation in the TRAIL pathway. Our fourth study investigated Ferrocene incorporated thiourea (FIT) as a better antileukemic agent than doxorubicin, as evidenced by STMN1 gene expression. Ferrocene-incorporated thiourea demonstrated a promising ability as an antiproliferative agent by downregulating NF-κB component Rel-A and as an apoptotic inducer by downregulating TRAIL inhibitor FLIP-L.