8th World Congress on

Cancer Research and Oncology

THEME: "Advancing Innovation and Collaboration in Cancer Research for a Healthier Tomorrow"

img2 23-24 Nov 2026
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Nur Azzalia Kamaruzaman

Nur Azzalia Kamaruzaman

Universiti Sains Malaysia, Malaysia

Title: New ?-Carboline Derivatives as Selective Chronic Myelogenous Leukemia (CML) Therapeutics: Harnessing Caspase-Independent Apoptosis to Overcome Resistance and Toxicity

Biography

Dr. Nur Azzalia Kamaruzaman is a Senior Lecturer and Director of the National Poison Centre, Universiti Sains Malaysia (USM), Malaysia’s sole poison centre. She holds a First Class Honours degree in Biotechnology (Drug Design and Development) from The University of Queensland, Australia, and a PhD from USM specialising in anticancer and genotoxicity research. Her research focuses on cancer biology and therapeutics, particularly the discovery and mechanistic evaluation of novel anticancer compounds using cellular and molecular approaches. Her work is supported by national and international research grants and published in peer-reviewed indexed journals. She has received multiple awards for research innovation and science communication, including international innovation medals. Notably, she was selected as one of six young Malaysian scientists to participate in the prestigious 71st Lindau Nobel Laureate Meeting in Germany. Beyond cancer research, she leads national and international initiatives in toxicology and public health.

Abstract

Chronic myelogenous leukemia (CML), driven by the BCR-ABL1 oncoprotein, responds initially to tyrosine kinase inhibitors (TKIs) such as imatinib. However, resistance, particularly T315I mutations, and treatment-related adverse effects limit long-term efficacy, highlighting the need for safer alternatives with resistance-bypassing mechanisms. ?-Carboline alkaloids represent a promising natural product-derived scaffold with multifunctional bioactivity. This study reports the synthesis and in vitro evaluation of novel ?-carboline derivatives as selective antileukemic agents targeting CML K562 cells through caspase-independent apoptosis. Compounds were synthesized using an optimized, low-waste Pictet–Spengler reaction (>80% yields), with purity confirmed by GC-MS and NMR. MTT screening against K562, HT-29, HeLa and HepG2 cancer cells and non-malignant Hs27 and BALB/c3T3 fibroblasts identified potent compounds, with IC?? values of 0.80 ?M (M25), 0.78 ?M (M56) and 0.123 ?M (M62) in K562 cells. Selectivity indices ranged from 2.9–42.53, demonstrating favourable selectivity compared with reference controls. Time-course assays demonstrated concentration- and time-dependent cytotoxicity, while morphological changes and Annexin V/PI flow cytometry confirmed apoptosis as the predominant mechanism. Caspase-3/7 activity showed no significant upregulation, supporting a caspase-independent apoptotic pathway. RT-qPCR and Western blot analyses demonstrated increased expression of apoptosis-inducing factor (AIF) and endonuclease G (EndoG), alongside caspase-9 activation and G0/G1 cell-cycle arrest. In silico docking further supported interactions with AIF, EndoG and apoptosis-related caspases. These findings indicate mitochondrial AIF/EndoG-mediated apoptosis as a potential mechanism acting downstream of BCR-ABL signalling and therefore potentially bypassing conventional TKI resistance mechanisms. Importantly, Ames and cell transformation assays demonstrated non-mutagenic and non-carcinogenic profiles under the tested conditions, providing additional evidence supporting their safety. Collectively, these findings identify ?-carboline derivatives, particularly M25, M56 and M62, as promising selective CML candidates and provide a strong rationale for further mechanistic, pharmacological and preclinical investigation toward the development of safer therapeutic strategies for resistant CML.

Keywords

Cancer; AIF; Chemotherapy; Apoptosis; Synthesis; Cytotoxicity