A novel stereo bioactive metabolite isolated from an endophytic fungus induces caspase dependent apoptosis and STAT-3 inhibition in human leukemia cells.
The present study describes the anti-leukemic potential of a novel stereo bioactive secondary metabolite, (R)-5-hydroxy-2-methylchroman-4-one (HMC) isolated from a novel endophytic fungus source (Cryptosporiopsis sp. H2-1, NFCCI-2856), associated with Clidemia hirta. HMC inhibited cell proliferation of different cancer cell lines with IC50 values in the range of 8-55 µg/ml. The cytotoxicity window of HMC was 6-12 times lower in normal cells as compared to susceptible leukemic HL-60, MOLT-4 and K-562 cells. It persuades apoptosis through both intrinsic and extrinsic pathways in above leukemic cell lines, which was evident through Hoechst staining, Annexin-V binding, cell cycle analysis, loss of mitochondrial membrane potential (Δψm), release of cytochrome c, Bax, Bid, over-expression of apical death receptors, activation of caspase-3,-8,-9 and PARP (poly ADP ribose polymerase) cleavage. HMC induced caspase dependent apoptosis and robustly attenuate transcription factor, p-STAT-3 in myeloid and lymphoid leukemia cells. The mechanism of HMC arbitrated inhibition of p-STAT-3 was due to the activation of ubiquitin dependent degradation of p-STAT-3. Therefore, our study not only describes the anti-leukemic potential of HMC but also provides insights into how endophytes can be useful in discovery and development of novel anticancer therapeutics.
Division of Cancer Pharmacology, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India; Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, New Delhi, India.
Anup Singh
AS
Pathania
Division of Cancer Pharmacology, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India.
Santosh Kumar
SK
Guru
PK-PD-Toxicology Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India; Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, New Delhi, India.
Nissar
N
Ul Ashraf
Microbial Biotechnology Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India; Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, New Delhi, India.
Syed
S
Riyaz-Ul-Hassan
Natural Product Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India; Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, New Delhi, India.
Asif
A
Ali
PK-PD-Toxicology Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India; Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, New Delhi, India.
Sheikh
S
Abdullah Tasduq
Division of Cancer Pharmacology, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India; Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, New Delhi, India.
Fayaz
F
Malik
Division of Cancer Pharmacology, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India; Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, New Delhi, India. Electronic address: sbhushan@iiim.ac.in.
Shashi
S
Bhushan
D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D020169:Caspases / Q000096:biosynthesis*; D003457:Cryptosporidiosis; D003458:Cryptosporidium / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D060026:Endophytes / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects / Q000502:physiology; D018922:HL-60 Cells; D006801:Humans; D020014:K562 Cells; D007938:Leukemia / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013237:Stereoisomerism
D000970:Antineoplastic Agents; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D020169:Caspases
(R)-5-hydroxy-2-methylchroman-4-one (HMC); Apoptosis; Endophyte; Proteosome inhibitor; STAT-3