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A novel quinazolinone chalcone derivative induces mitochondrial dependent apoptosis and inhibits PI3K/Akt/mTOR signaling pathway in human colon cancer HCT-116 cells |
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| Institution: | 1. Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India;2. Plant Biotechnology Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India;3. Natural Product Microbes Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India;4. Department of Biochemistry, Jamia Hamdard (Hamdard University), New Delhi 110062, India |
| Abstract: | We have synthesized a novel quinazolinone chalcone derivative (QC) and first time reported its in-vitro and in-vivo anticancer potential. It inhibited the cell proliferation of different cancer cell lines like PC-3, Panc-1, Mia-Paca-2, A549, MCF-7 and HCT-116. It induces apoptosis as measured by several biological endpoints such as apoptotic body formation, evident by Hoechst and scanning electron microscopy, enhanced annexinV-FITC binding of the cells, increased sub-G0 cell fraction, loss of mitochondrial membrane potential (Δψm), reduction of Bcl-2/Bax ratio, activation of caspase-9, caspase-3 and PARP-1 (poly-ADP Ribose polymerase) cleavage in HCT-116 cells. In spite of apoptosis, QC significantly hammers the downstream and upstream signaling cascade of PI3K/Akt/mTOR pathway and cell cycle regulator Skp-2, p21 and p27. Interestingly, QC induces the S and G2/M phase of HCT-116 cells at experimental doses. QC inhibits the tumor growth of Ehrlich ascites carcinoma (EAC), Ehrlich tumor (ET, solid) and sarcoma-180(solid) mice models. Furthermore, it was found to be non-toxic as no animal mortality (0/7) occurred during experimental doses. The present study provides an insight of anticancer potential of QC, which may be useful in managing and treating cancer. |
| Keywords: | Quinazolinone-chalcone Apoptosis PI3K/Akt/mTOR Sarcoma-180 QC"} {"#name":"keyword" "$":{"id":"kwrd0035"} "$$":[{"#name":"text" "_":"Quinazolinone-chalcone Δψm"} {"#name":"keyword" "$":{"id":"kwrd0045"} "$$":[{"#name":"text" "_":"mitochondrial membrane potential MTT"} {"#name":"keyword" "$":{"id":"kwrd0055"} "$$":[{"#name":"text" "_":"3-(4 5-dimethylthiazole-2-yl)-2 5-diphenyltetrazolium bromide PI"} {"#name":"keyword" "$":{"id":"kwrd0065"} "$$":[{"#name":"text" "_":"propidium iodide PTP"} {"#name":"keyword" "$":{"id":"kwrd0075"} "$$":[{"#name":"text" "_":"mitochondrial permeability transition pore Rh-123"} {"#name":"keyword" "$":{"id":"kwrd0085"} "$$":[{"#name":"text" "_":"Rhodamine- 123 PBS"} {"#name":"keyword" "$":{"id":"kwrd0095"} "$$":[{"#name":"text" "_":"phosphate buffer saline PARP"} {"#name":"keyword" "$":{"id":"kwrd0105"} "$$":[{"#name":"text" "_":"poly-ADP-ribose polymerase mTOR"} {"#name":"keyword" "$":{"id":"kwrd0115"} "$$":[{"#name":"text" "_":"mammalian target of rapamycin DMEM"} {"#name":"keyword" "$":{"id":"kwrd0125"} "$$":[{"#name":"text" "_":"Dulbecco's Modified Eagle's medium RPMI"} {"#name":"keyword" "$":{"id":"kwrd0135"} "$$":[{"#name":"text" "_":"Roswell Park Memorial Institute MEM"} {"#name":"keyword" "$":{"id":"kwrd0145"} "$$":[{"#name":"text" "_":"Minimum Essential Medium EAC"} {"#name":"keyword" "$":{"id":"kwrd0155"} "$$":[{"#name":"text" "_":"Ehrlich Ascites Carcinoma ET"} {"#name":"keyword" "$":{"id":"kwrd0165"} "$$":[{"#name":"text" "_":"Ehrlich Ascites tumor S-180"} {"#name":"keyword" "$":{"id":"kwrd0175"} "$$":[{"#name":"text" "_":"sarcoma-180 |
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