Isoledene from Mesua ferrea oleo-gum resin induces apoptosis in HCT 116 cells through ROS-mediated modulation of multiple proteins in the apoptotic pathways: A mechanistic study.
Colorectal cancer (CRC) is one of the most common human malignant tumors worldwide. Arising from the transformation of epithelial cells in the colon and/or rectum into malignant cells, the foundation of CRC pathogenesis lies in the progressive accumulation of mutations in oncogenes and tumor-suppressor genes, such as KRAS and APC. Resistance to apoptosis is one of the key mechanisms in the development of CRC as it is for any other kind of cancer. Natural products have been shown to induce the expression of apoptosis regulators that are blocked in cancer cells. In the present study, a series of in vitro assays were employed to study the apoptosis-inducing attributes of Isoledene rich sub-fraction (IR-SF) collected from the oleo-gum resin of M. ferrea. Data obtained, showed that IR-SF inhibited cell proliferation and induced typical apoptotic changes in the overall morphology of all the CRC cell lines tested. Fluorescent staining assays revealed characteristic nuclear condensation, and marked decrease in mitochondrial outer membrane potential in the treated cells. In addition, an increment in the levels of ROS, caspase-8, -9 and -3 was observed. Proteomic analysis revealed that IR-SF up-regulated the expression of pro-apoptotic proteins, i.e., Bid, Bim and cytochrome c. Cytochrome c in turn activated caspases cascade resulting in the induction of apoptosis. Moreover, IR-SF significantly down-regulated Bcl-2, Bcl-w, survivin, xIAP and HSPs pro-survival proteins and induced DNA fragmentation and G0/G1-phase arrest in HCT 116 cells. Chemical characterization of IR-SF by GC-MS and HPLC methods identified Isoledene as one of the major compounds. Altogether, results of the present study demonstrate that IR-SF may induce apoptosis in human colorectal carcinoma cells through activation of ROS-mediated apoptotic pathways.
EMAN Testing and Research Laboratory, Department of Pharmacology, School of Pharmaceutical Sciences, Universti Sains Malaysia, Penang 11800, Malaysia. Electronic address: asif_pharmacist45@yahoo.com.
Muhammad
M
Asif
Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Universti Sains Malaysia, Penang 11800, Malaysia.
Armaghan
A
Shafaei
EMAN Testing and Research Laboratory, Department of Pharmacology, School of Pharmaceutical Sciences, Universti Sains Malaysia, Penang 11800, Malaysia.
Seyedeh Fatemeh
SF
Jafari
EMAN Testing and Research Laboratory, Department of Pharmacology, School of Pharmaceutical Sciences, Universti Sains Malaysia, Penang 11800, Malaysia.
Shazmin Kithur
SK
Mohamed
Centre for Drug Research, Universti Sains Malaysia, Penang 11800, Malaysia.
Mohammed Oday
MO
Ezzat
Department of Pharmacology, School of Medical Sciences, Quest International University, Perak, Malaysia.
Aman Shah
AS
Abdul Majid
Institute for Research in Molecular Medicine (INFORMM), Universti Sains Malaysia, Penang 11800, Malaysia.
Chern Ein
CE
Oon
Cancer Science Institute of Singapore, National University of Singapore, Singapore.
Sven H
SH
Petersen
Cancer Science Institute of Singapore, National University of Singapore, Singapore; Department of Surgery, National University of Singapore, Singapore.
Koji
K
Kono
EMAN Testing and Research Laboratory, Department of Pharmacology, School of Pharmaceutical Sciences, Universti Sains Malaysia, Penang 11800, Malaysia. Electronic address: Aminmalikshah@gmail.com.
Amin Malik Shah
AM
Abdul Majid
D000972:Antineoplastic Agents, Phytogenic / Q000302:isolation & purification / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D045325:HCT116 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D019684:Magnoliopsida / Q000737:chemistry; D018384:Oxidative Stress / Q000187:drug effects*; D008517:Phytotherapy; D010946:Plants, Medicinal; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012116:Resins, Plant / Q000302:isolation & purification / Q000494:pharmacology*; D012717:Sesquiterpenes / Q000302:isolation & purification / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
D000972:Antineoplastic Agents, Phytogenic; D051017:Apoptosis Regulatory Proteins; D017382:Reactive Oxygen Species; D012116:Resins, Plant; D012717:Sesquiterpenes; C000613949:isoledene
Bid; Bim; Colorectal cancer; Isoledene; Mesua ferrea; ROS; Survivin; xIAP