CARP-1 functional mimetics: a novel class of small molecule inhibitors of cancer cell growth and metastasis

CARP-1 functional mimetics: a novel class of small molecule inhibitors of cancer cell growth and metastasis

CARP-1/CCAR1 is a peri-nuclear phospho-protein which functions as a co-activator of the cell cycle regulatory anaphase promoting complex/cyclosome (APC/C) E3 ligase. CARP-1 functional mimetics (CFMs) are a class of small molecule compounds that inhibit CARP-1 binding with APC/C subunit APC-2. CFM-4,...

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Main Author: Ashour, Abdelkader Elbadawy Abbas
Format: Conference or Workshop Item
Language:English
English
English
Published: 2019
Subjects:
RM300 Drugs and their action
Online Access:http://irep.iium.edu.my/78960/
http://irep.iium.edu.my/78960/1/Dr.%20Abdelkader%20Ashour%20Keynote%20Speaker.pdf
http://irep.iium.edu.my/78960/2/Pharmacology%202019_Book%20Final.pdf
http://irep.iium.edu.my/78960/13/CARP-1%20functional%20mimetics%20A%20novel%20class%20of%20small%20molecule%20inhibitors%20of%20cancer%20cell%20growth%20and%20metastasis%20F.pdf
id iium-78960
recordtype eprints
repository_type Digital Repository
institution_category Local University
institution International Islamic University Malaysia
building IIUM Repository
collection Online Access
language English
English
English
topic RM300 Drugs and their action
spellingShingle RM300 Drugs and their action
Ashour, Abdelkader Elbadawy Abbas
CARP-1 functional mimetics: a novel class of small molecule inhibitors of cancer cell growth and metastasis
description CARP-1/CCAR1 is a peri-nuclear phospho-protein which functions as a co-activator of the cell cycle regulatory anaphase promoting complex/cyclosome (APC/C) E3 ligase. CARP-1 functional mimetics (CFMs) are a class of small molecule compounds that inhibit CARP-1 binding with APC/C subunit APC-2. CFM-4, a lead compound, was found to be a potent antitumor agent that suppresses growth and metastasis of various tumor cells including medulloblastoma, neuroblastoma, malignant pleural mesothelioma, lung and breast cancers, in part by stimulating apoptosis. Recently, we examined the possible inhibitory effects CFM-4 against proliferation and metastasis of colorectal cancer (CRC). CRC constitutes one of the most aggressive malignancies worldwide. Existing anti-tumor treatments clinically applied for CRC include surgery, radiotherapy and chemotherapy. The high incidence of metastasis and toxic side effects of therapies, as well as low response rates of CRC to chemotherapy indicate that existing treatment methodologies remain unsatisfactory. Thus, it is crucial to develop more efficient and less noxious treatment modalities for this disease. In this recent study, we investigated the growth inhibitory potential of the CFM-4 on CRC and found that CFM-4 inhibits colon cancer cell proliferation in a dose and time dependent manner. Notably, CFM-4 was much more potent than the classical anti-colorectal cancer 5-fluorouracil. The growth inhibitory effects of CFM-4 against CRC cells were mediated at least in part by stimulating apoptosis, as indicated in our Annexin V/Propidium iodide (PI) apoptosis assay results. To molecularly assess the effects of CFM-4 as antitumor agent against human colorectal HT-29 cells, mRNA expression analysis by qPCR was also utilized. Results revealed upregulation of expression of caspase-8 and caspase-9, as well as p53 and its downstream targets, PUMA, Noxa, Smac which play a crucial part in promoting mitochondrial apoptotic pathway. Pro-apoptotic molecules known to initiate the extrinsic apoptotic pathway including TRAIL death receptors (DR4 and DR5) were also upregulated. These results suggest that CFM-4 induces both intrinsic and extrinsic pathways of apoptosis. The influence of CFM-4 on mRNA expression of the NF-B signaling inhibitor A20-binding inhibitor protein (ABIN1) was also assessed and revealed upregulated. Although CFM-4 did not significantly affect the expression of the PI3K downstream effector AKT, it remarkably upregulated the PI3K negative regulator PTEN. Moreover, we examined CFM-4 effects on colon cancer cell cycle and observed that CFM-4 has significantly induced G2/M phase arrest and dose-dependent increase in sub-G1 peak, indicative of apoptosis, of the cell cycle of the colon cancer HT-29 cells, further substantiating our Annexin V/PI apoptosis results. Furthermore, western blot analysis results revealed that CFM-4 enhanced expression of CARP-1, as well as the initiator caspase, caspase-8, and the executioner caspase, caspase-3. On the other hand, metastatic properties of the HT-29 CRC cells were reduced by CFM-4 through blocking their capabilities to form colonies, migrate and invade through the matrix-coated membranes. These results revealed that the potent antitumor and anti-metastatic properties of CFM-4 against CRC are due to collective pro-apoptotic, anti-proliferative and anti-invasive activities. Together our data warrants further investigations of CFM-4 as potential anti-tumor agent for CRC malignancy and metastasis.
format Conference or Workshop Item
author Ashour, Abdelkader Elbadawy Abbas
author_facet Ashour, Abdelkader Elbadawy Abbas
author_sort Ashour, Abdelkader Elbadawy Abbas
title CARP-1 functional mimetics: a novel class of small molecule inhibitors of cancer cell growth and metastasis
title_short CARP-1 functional mimetics: a novel class of small molecule inhibitors of cancer cell growth and metastasis
title_full CARP-1 functional mimetics: a novel class of small molecule inhibitors of cancer cell growth and metastasis
title_fullStr CARP-1 functional mimetics: a novel class of small molecule inhibitors of cancer cell growth and metastasis
title_full_unstemmed CARP-1 functional mimetics: a novel class of small molecule inhibitors of cancer cell growth and metastasis
title_sort carp-1 functional mimetics: a novel class of small molecule inhibitors of cancer cell growth and metastasis
publishDate 2019
url http://irep.iium.edu.my/78960/
http://irep.iium.edu.my/78960/1/Dr.%20Abdelkader%20Ashour%20Keynote%20Speaker.pdf
http://irep.iium.edu.my/78960/2/Pharmacology%202019_Book%20Final.pdf
http://irep.iium.edu.my/78960/13/CARP-1%20functional%20mimetics%20A%20novel%20class%20of%20small%20molecule%20inhibitors%20of%20cancer%20cell%20growth%20and%20metastasis%20F.pdf
first_indexed 2023-09-18T21:51:07Z
last_indexed 2023-09-18T21:51:07Z
_version_ 1777413775839723520
spelling iium-789602020-02-27T07:50:40Z http://irep.iium.edu.my/78960/ CARP-1 functional mimetics: a novel class of small molecule inhibitors of cancer cell growth and metastasis Ashour, Abdelkader Elbadawy Abbas RM300 Drugs and their action CARP-1/CCAR1 is a peri-nuclear phospho-protein which functions as a co-activator of the cell cycle regulatory anaphase promoting complex/cyclosome (APC/C) E3 ligase. CARP-1 functional mimetics (CFMs) are a class of small molecule compounds that inhibit CARP-1 binding with APC/C subunit APC-2. CFM-4, a lead compound, was found to be a potent antitumor agent that suppresses growth and metastasis of various tumor cells including medulloblastoma, neuroblastoma, malignant pleural mesothelioma, lung and breast cancers, in part by stimulating apoptosis. Recently, we examined the possible inhibitory effects CFM-4 against proliferation and metastasis of colorectal cancer (CRC). CRC constitutes one of the most aggressive malignancies worldwide. Existing anti-tumor treatments clinically applied for CRC include surgery, radiotherapy and chemotherapy. The high incidence of metastasis and toxic side effects of therapies, as well as low response rates of CRC to chemotherapy indicate that existing treatment methodologies remain unsatisfactory. Thus, it is crucial to develop more efficient and less noxious treatment modalities for this disease. In this recent study, we investigated the growth inhibitory potential of the CFM-4 on CRC and found that CFM-4 inhibits colon cancer cell proliferation in a dose and time dependent manner. Notably, CFM-4 was much more potent than the classical anti-colorectal cancer 5-fluorouracil. The growth inhibitory effects of CFM-4 against CRC cells were mediated at least in part by stimulating apoptosis, as indicated in our Annexin V/Propidium iodide (PI) apoptosis assay results. To molecularly assess the effects of CFM-4 as antitumor agent against human colorectal HT-29 cells, mRNA expression analysis by qPCR was also utilized. Results revealed upregulation of expression of caspase-8 and caspase-9, as well as p53 and its downstream targets, PUMA, Noxa, Smac which play a crucial part in promoting mitochondrial apoptotic pathway. Pro-apoptotic molecules known to initiate the extrinsic apoptotic pathway including TRAIL death receptors (DR4 and DR5) were also upregulated. These results suggest that CFM-4 induces both intrinsic and extrinsic pathways of apoptosis. The influence of CFM-4 on mRNA expression of the NF-B signaling inhibitor A20-binding inhibitor protein (ABIN1) was also assessed and revealed upregulated. Although CFM-4 did not significantly affect the expression of the PI3K downstream effector AKT, it remarkably upregulated the PI3K negative regulator PTEN. Moreover, we examined CFM-4 effects on colon cancer cell cycle and observed that CFM-4 has significantly induced G2/M phase arrest and dose-dependent increase in sub-G1 peak, indicative of apoptosis, of the cell cycle of the colon cancer HT-29 cells, further substantiating our Annexin V/PI apoptosis results. Furthermore, western blot analysis results revealed that CFM-4 enhanced expression of CARP-1, as well as the initiator caspase, caspase-8, and the executioner caspase, caspase-3. On the other hand, metastatic properties of the HT-29 CRC cells were reduced by CFM-4 through blocking their capabilities to form colonies, migrate and invade through the matrix-coated membranes. These results revealed that the potent antitumor and anti-metastatic properties of CFM-4 against CRC are due to collective pro-apoptotic, anti-proliferative and anti-invasive activities. Together our data warrants further investigations of CFM-4 as potential anti-tumor agent for CRC malignancy and metastasis. 2019-09-11 Conference or Workshop Item NonPeerReviewed application/pdf en http://irep.iium.edu.my/78960/1/Dr.%20Abdelkader%20Ashour%20Keynote%20Speaker.pdf application/pdf en http://irep.iium.edu.my/78960/2/Pharmacology%202019_Book%20Final.pdf application/pdf en http://irep.iium.edu.my/78960/13/CARP-1%20functional%20mimetics%20A%20novel%20class%20of%20small%20molecule%20inhibitors%20of%20cancer%20cell%20growth%20and%20metastasis%20F.pdf Ashour, Abdelkader Elbadawy Abbas (2019) CARP-1 functional mimetics: a novel class of small molecule inhibitors of cancer cell growth and metastasis. In: 14th World Congress on Pharmacology, Toxicology and Drug Discovery, 11th September 2019, Singapore. (Unpublished)

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