The Experts below are selected from a list of 315 Experts worldwide ranked by ideXlab platform
Junaid Abdulghani - One of the best experts on this subject based on the ideXlab platform.
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sorafenib and Quinacrine target anti apoptotic protein mcl1 a poor prognostic marker in anaplastic thyroid cancer atc
Clinical Cancer Research, 2016Co-Authors: Jeannicolas Gallant, Junaid Abdulghani, David T Dicker, Prashanth Gokare, Tiffany L Whitcomb, Timothy K Cooper, Jiangang LiaoAbstract:Purpose: Anaplastic thyroid cancer (ATC) comprises ~2% of all thyroid cancers and its median survival rate remains poor. It is responsible for more than one-third of thyroid cancer-related deaths. ATC is frequently resistant to conventional therapy and NFkappaB-signaling has been proposed to be a feature of the disease. We aimed to assess the activity of the anti-malaria drug Quinacrine known to target NFkappaB-signaling in combination with the clinically relevant kinase inhibitor sorafenib in ATC cells. The presence of NFkappaB-p65/RelA and its target Mcl-1 was demonstrated in ATC by meta-data gene set enrichment analysis and immunohistochemistry (IHC). We assessed the responses of a panel of human ATC cell lines to Quinacrine and sorafenib in vitro and in vivo. Results: We detected increased expression of NFkappaB-p65/RelA and Mcl-1 in the nucleus of a subset of ATC compared to non-neoplastic thyroid. ATC-cells were found to respond with additive/synergistic tumor cell-killing to the combination of sorafenib plus Quinacrine in vitro and the drug combination improves survival of immunodeficient mice injected orthotopically with ATC-cells as compared to mice administered either compound alone or doxorubicin. We also demonstrate that the combination of sorafenib and Quinacrine is well tolerated in mice. At the molecular level, Quinacrine and sorafenib inhibited expression of the pro-survival gene Mcl-1, pStat3 and dampened NFkappaB signaling. Conclusion: The combination of Quinacrine and sorafenib targets emerging molecular hallmarks of ATC and shows promising results in clinically relevant models for the disease. Further testing of sorafenib plus Quinacrine can be conducted in ATC patients.
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sorafenib and Quinacrine target anti apoptotic protein mcl1 a poor prognostic marker in anaplastic thyroid cancer atc
Clinical Cancer Research, 2016Co-Authors: Jeannicolas Gallant, Junaid Abdulghani, David T Dicker, Prashanth Gokare, Tiffany L Whitcomb, Timothy K Cooper, Jiangang LiaoAbstract:Purpose and Experimental Design: Anaplastic thyroid cancer (ATC) comprises approximately 2% of all thyroid cancers, and its median survival rate remains poor. It is responsible for more than one third of thyroid cancer–related deaths. ATC is frequently resistant to conventional therapy, and NFκB signaling has been proposed to be a feature of the disease. We aimed to assess the activity of the antimalaria drug Quinacrine known to target NFκB signaling in combination with the clinically relevant kinase inhibitor sorafenib in ATC cells. The presence of NFκB-p65/RELA and its target MCL1 was demonstrated in ATC by meta-data gene set enrichment analysis and IHC. We assessed the responses of a panel of human ATC cell lines to Quinacrine and sorafenib in vitro and in vivo. Results: We detected increased expression of NFκB-p65/RELA and MCL1 in the nucleus of a subset of ATC compared with non-neoplastic thyroid. ATC cells were found to respond with additive/synergistic tumor cell killing to the combination of sorafenib plus Quinacrine in vitro, and the drug combination improves survival of immunodeficient mice injected orthotopically with ATC cells as compared with mice administered either compound alone or doxorubicin. We also demonstrate that the combination of sorafenib and Quinacrine is well tolerated in mice. At the molecular level, Quinacrine and sorafenib inhibited expression of prosurvival MCL1, pSTAT3, and dampened NFκB signaling. Conclusions: The combination of Quinacrine and sorafenib targets emerging molecular hallmarks of ATC and shows promising results in clinically relevant models for the disease. Further testing of sorafenib plus Quinacrine can be conducted in ATC patients. Clin Cancer Res; 22(24); 6192–203. ©2016 AACR.
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abstract 2527 the drug combination sorafenib and Quinacrine targets the expression of mcl 1 an anti apoptotic protein and candidate prognostic factor in anaplastic thyroid cancer atc
Cancer Research, 2015Co-Authors: Junaid Abdulghani, Prashanth Gokare, Tiffany L Whitcomb, Timothy K Cooper, Jiangang Liao, Jeannicholas Gallant, David M Goldenberg, Niklas Finnberg, Wafik S EldeiryAbstract:Anaplastic thyroid cancer (ATC) is a rare, highly aggressive form of thyroid cancer that frequently is resistant to conventional therapy and therefore requires the development of efficacious novel therapy. Sorafenib, a multi-kinase inhibitor that inhibits the RAF, MEK and ERK kinases, was recently approved by the FDA for late stage metastatic differentiated thyroid cancer but appears to have limited activity in ATC by itself. Sorafenib-based drug combinations with complimentary drug targets are being pursued and evaluated preclinically. However, sorafenib generates a significant number of adverse events in thyroid cancer patients and drug combinations including sorafenib needs to be carefully tailored with respect to toxicity and efficacy. We have previously shown that Quinacrine, a potent small molecule inhibitor of NFKB signaling, combine favorably with several cytotoxic drugs to target hepatocellular and colorectal cancer cells. Quinacrine is an inexpensive drug, has a well established safety profile in human subjects and is being evaluated in cancer clinical trials. Subsequently, we decided to evaluate the efficacy of the drug combination of Quinacrine and sorafenib in ATC. Our combinatorial dose-response modulation of Quinacrine with sorafenib suggests a synergistic drug-drug interaction with respect to growth stasis in a panel of ATC cells in vitro, as defined by Chou-Talalay. Furthermore, in vivo the drug combination of sorafenib and Quinacrine significantly improved survival compared to vehicle control and the current first line chemotherapeutic doxorubicin in a mouse thyroid orthotopic xenograft model of ATC. Dose-escalation toxicity studies in mice suggest that the drug combination was well tolerated and did not trigger synergistic toxicities compared to either drug alone. Significantly less gastrointestinal injury, the most commonly observed toxicity in our study, was present following treatment with the drug combination of sorafenib and Quinacrine compared to treatment with doxorubicin alone. Western blot analysis suggests that the anti-apoptotic Bcl-2 family member Mcl-1 is a target for the drug combination. Indeed, immunohistochemical (IHC) analysis of resected ATC and non-neoplastic thyroid tissues from patients confirmed overexpression of Mcl-1 in ATC indicating target availability. Interestingly, multi-regression analysis of our patient IHC data suggest that high Mcl-1 expression together with tumor size prognosticated poor survival in ATC patients suggesting that Mcl-1 overexpression was linked to a more aggressive tumor behavior. In conclusion, our findings suggest that Quinacrine in combination with sorafenib may be a novel and potentially cost effective therapeutic strategy to target Mcl-1, whose expression potentially may be linked to the disease progression of ATC. Citation Format: Junaid Abdulghani, Jean-Nicholas Gallant, Prashanth Gokare, Timothy Cooper, Tiffany Whitcomb, Jiangang Liao, Jing Liu, David Goldenberg, Niklas K. Finnberg, Wafik S. El-Deiry. The drug combination sorafenib and Quinacrine targets the expression of Mcl-1 - an anti-apoptotic protein and candidate prognostic factor in Anaplastic Thyroid Cancer (ATC). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2527. doi:10.1158/1538-7445.AM2015-2527
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Quinacrine sensitizes hepatocellular carcinoma cells to trail and chemotherapeutic agents
Cancer Biology & Therapy, 2011Co-Authors: Wenge Wang, Jeannicolas Gallant, Sharyn I Katz, Nathan G Dolloff, Charles D Smith, Junaid Abdulghani, Joshua E Allen, David T DickerAbstract:Quinacrine has been widely explored in treatment of malaria, giardiasis, and rheumatic diseases. We find that Quinacrine stabilizes p53 and induces p53-dependent and independent cell death. Treatment by Quinacrine alone at concentrations of 10–20 mM for 1–2 d cannot kill hepatocellular carcinoma cells, such as HepG2, Hep3B, Huh7, which are also resistant to TRAIL. However, Quinacrine renders these cells sensitive to treatment by TRAIL. Co-treatment of these cells with Quinacrine and TRAIL induces overwhelming cell death within 3–4 h. Levels of DR5, a pro-apoptotic death receptor of TRAIL, are increased upon treatment with Quinacrine, while levels of Mcl-1, an anti-apoptotic member of the Bcl-2 family, are decreased. While the synergistic effect of Quinacrine with TRAIL appears to be in part independent of p53, knockdown of p53 in HepG2 cells by siRNA results in more cell death after treatment by Quinacrine and TRAIL. The mechanism by which Quinacrine sensitizes hepatocellular carcinoma cells to TRAIL and ...
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abstract 680 Quinacrine sensitizes hepatocellular carcinoma cells to trail via up regulating dr5 and eradicating mcl 1
Cancer Research, 2010Co-Authors: W T Wang, Sharyn I Katz, Junaid Abdulghani, David T Dicker, Wafik S EldeiryAbstract:Quinacrine has been widely explored in treatment of malaria, giardiasis, and rheumatic diseases. We find that Quinacrine stabilizes p53 and induces p53-dependent and independent tumor cell death. Structurally, Quinacrine bears similar characteristics with DNA-intercalating agents. Indeed, Quinacrine competes with Propidium Iodide and shows a high binding affinity to DNA. Interestingly, Quinacrine is a fluorescent dye that can be visualized under a laser microscope. In live cells, Quinacrine is mainly clustered in the cytoplasm with a faint fluorescent signal in the nucleus. If the cells are fixed with methanol, Quinacrine accumulates predominantly in the nucleus. Treatment by Quinacrine alone at concentrations of 10-20 μM for 1-2 days can not kill hepatocellular carcinoma cells, such as HepG2, Hep3B, Huh7, which are also resistant to TRAIL. However, Quinacrine renders these cells sensitive to treatment of TRAIL significantly. Co-treatment of these cells with Quinacrine and TRAIL induces overwhelming cell death in 3-4 hr. Western blotting shows the level of DR5, a pro-apoptotic death receptor of TRAIL, is increased while MCL-1, a member of the Bcl-2 family, is decreased. While the synergistic effect of Quinacrine with TRAIL appears to be in part independent of p53, knockdown of p53 in HepG2 cells by siRNA results in more cell death after treatment by Quinacrine and TRAIL. The mechanism of Quinacrine sensitization of hepatocellular carcinoma cells and the potential for clinical application are being further explored. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 680.
David T Dicker - One of the best experts on this subject based on the ideXlab platform.
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sorafenib and Quinacrine target anti apoptotic protein mcl1 a poor prognostic marker in anaplastic thyroid cancer atc
Clinical Cancer Research, 2016Co-Authors: Jeannicolas Gallant, Junaid Abdulghani, David T Dicker, Prashanth Gokare, Tiffany L Whitcomb, Timothy K Cooper, Jiangang LiaoAbstract:Purpose: Anaplastic thyroid cancer (ATC) comprises ~2% of all thyroid cancers and its median survival rate remains poor. It is responsible for more than one-third of thyroid cancer-related deaths. ATC is frequently resistant to conventional therapy and NFkappaB-signaling has been proposed to be a feature of the disease. We aimed to assess the activity of the anti-malaria drug Quinacrine known to target NFkappaB-signaling in combination with the clinically relevant kinase inhibitor sorafenib in ATC cells. The presence of NFkappaB-p65/RelA and its target Mcl-1 was demonstrated in ATC by meta-data gene set enrichment analysis and immunohistochemistry (IHC). We assessed the responses of a panel of human ATC cell lines to Quinacrine and sorafenib in vitro and in vivo. Results: We detected increased expression of NFkappaB-p65/RelA and Mcl-1 in the nucleus of a subset of ATC compared to non-neoplastic thyroid. ATC-cells were found to respond with additive/synergistic tumor cell-killing to the combination of sorafenib plus Quinacrine in vitro and the drug combination improves survival of immunodeficient mice injected orthotopically with ATC-cells as compared to mice administered either compound alone or doxorubicin. We also demonstrate that the combination of sorafenib and Quinacrine is well tolerated in mice. At the molecular level, Quinacrine and sorafenib inhibited expression of the pro-survival gene Mcl-1, pStat3 and dampened NFkappaB signaling. Conclusion: The combination of Quinacrine and sorafenib targets emerging molecular hallmarks of ATC and shows promising results in clinically relevant models for the disease. Further testing of sorafenib plus Quinacrine can be conducted in ATC patients.
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sorafenib and Quinacrine target anti apoptotic protein mcl1 a poor prognostic marker in anaplastic thyroid cancer atc
Clinical Cancer Research, 2016Co-Authors: Jeannicolas Gallant, Junaid Abdulghani, David T Dicker, Prashanth Gokare, Tiffany L Whitcomb, Timothy K Cooper, Jiangang LiaoAbstract:Purpose and Experimental Design: Anaplastic thyroid cancer (ATC) comprises approximately 2% of all thyroid cancers, and its median survival rate remains poor. It is responsible for more than one third of thyroid cancer–related deaths. ATC is frequently resistant to conventional therapy, and NFκB signaling has been proposed to be a feature of the disease. We aimed to assess the activity of the antimalaria drug Quinacrine known to target NFκB signaling in combination with the clinically relevant kinase inhibitor sorafenib in ATC cells. The presence of NFκB-p65/RELA and its target MCL1 was demonstrated in ATC by meta-data gene set enrichment analysis and IHC. We assessed the responses of a panel of human ATC cell lines to Quinacrine and sorafenib in vitro and in vivo. Results: We detected increased expression of NFκB-p65/RELA and MCL1 in the nucleus of a subset of ATC compared with non-neoplastic thyroid. ATC cells were found to respond with additive/synergistic tumor cell killing to the combination of sorafenib plus Quinacrine in vitro, and the drug combination improves survival of immunodeficient mice injected orthotopically with ATC cells as compared with mice administered either compound alone or doxorubicin. We also demonstrate that the combination of sorafenib and Quinacrine is well tolerated in mice. At the molecular level, Quinacrine and sorafenib inhibited expression of prosurvival MCL1, pSTAT3, and dampened NFκB signaling. Conclusions: The combination of Quinacrine and sorafenib targets emerging molecular hallmarks of ATC and shows promising results in clinically relevant models for the disease. Further testing of sorafenib plus Quinacrine can be conducted in ATC patients. Clin Cancer Res; 22(24); 6192–203. ©2016 AACR.
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abstract 3486 synergistic effect of Quinacrine in combination with decitabine for the treatment of acute myeloid leukemia cellsin vitro implication for treatment of aml in the elderly
Cancer Research, 2015Co-Authors: Wenge Wang, David T Dicker, David F Claxton, Hong Gang Wang, Wafik S EldeiryAbstract:Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Demethylating agents remain one of the few options for treatment of AML in the elderly; however, the response rate is limited. In searching for p53 pathway activating agents for cancer therapy, we found that Quinacrine is a potent p53 stimulator and induces tumor cell death. Quinacrine also induces expression of Death Receptor 5 (DR5), reduces expression of anti-apoptotic Mcl-1, and suppresses NFkB activity in tumor cells. Because of its acceptable toxicity profile, history of use in humans, and relevance of the target pathways modulated by Quinacrine we explored whether it may serve as a potent anti-leukemia drug as most leukemia cells carry a wild-type p53. We tested the cytotoxic effects of Quinacrine on malignant hematopoietic cell lines derived from patients with myeloid leukemia, including HL-60, MOLM-13, and MV4-11. We found that Quinacrine induces massive cell death in the cell lines tested, at concentrations from as less as 1 microM to 5 microM, 2-10 times lower than required to induce solid tumor cell death. Most interestingly, Quinacrine facilitates cell death in decitabine pre-treated leukemia cells in a synergistic manner. Further mechanistic studies showed that Quinacrine stabilizes p53, induces Mcl-1 degradation, and PARP cleavage in treated cells. Our work supports translational efforts to advance the use of Quinacrine from the bench to the clinic and provides a preliminary rationale for its combination with decitabine for the treatment of AML. Citation Format: Wenge Wang, David T. Dicker, David F. Claxton, Hong-Gang Wang, Wafik S. El-Deiry. Synergistic effect of Quinacrine in combination with decitabine for the treatment of acute myeloid leukemia cells in vitro : implication for treatment of AML in the elderly. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3486. doi:10.1158/1538-7445.AM2015-3486
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synergistic effect of Quinacrine with chemotherapeutics or trail in hematopoietic malignant cells
Blood, 2014Co-Authors: Wenge Wang, Nathan G Dolloff, David T Dicker, Amriti R Lulla, Liz J Hernandezborrero, Emmanuel K Teye, Mala K Talekar, Wafik S EldeiryAbstract:Abstract Quinacrine is a bioactive acridine derivative which has been used for treatment of malaria, giardiasis, systemic lupus erythematosus, and rheumatoid arthritis. In searching for p53 pathway activating agents for cancer therapy, we found that Quinacrine stabilizes p53 and induces p53-dependent and p53-independent tumor cell death. Quinacrine also induces expression of TRAIL Death Receptor 5 (DR5) and reduces expression of anti-apoptotic Mcl-1 in tumor cells. These activities predict synergies with TRAIL (tumor necrosis factor-related apoptosis inducing ligand) and chemotherapeutic agents in inducing extrinsic and intrinsic pathway mediated apoptosis. In addition, Quinacrine suppresses NFkB activity in tumor cells. Clinical trials have been ongoing for treatment of solid tumors including colon cancer, renal cancer, prostate cancer, and non-small cell lung cancer with Quinacrine in combination with chemotherapy or tyrosine-kinase inhibitors, however, the therapeutic potential of Quinacrine in blood cancer cells has not been established. We tested Quinacrine on hematopoietic malignant cells, which included cell lines of myeloid leukemia, lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, and multiple myeloma. We found that Quinacrine induces massive cell death in the cell lines tested, at concentrations from as less as 1 microM to 5 microM, 2-10 times lower than required to induce solid tumor cell death. Quinacrine synergizes with TRAIL in inducing cell death of TRAIL-sensitive cells and reverses resistance in TRAIL-resistant cells. Quinacrine also synergizes with chemotherapeutic agents, such as antimetabolites, alkylating agents, and tyrosine kinase inhibitors, in inducing apoptosis of hematopoietic cancer cell lines. Our work supports translational efforts to advance the use of Quinacrine from bench to clinic and provides rationale for combination chemotherapeutic regimes for treatment of hematopoietic malignancies. Disclosures No relevant conflicts of interest to declare.
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Quinacrine sensitizes hepatocellular carcinoma cells to trail and chemotherapeutic agents
Cancer Biology & Therapy, 2011Co-Authors: Wenge Wang, Jeannicolas Gallant, Sharyn I Katz, Nathan G Dolloff, Charles D Smith, Junaid Abdulghani, Joshua E Allen, David T DickerAbstract:Quinacrine has been widely explored in treatment of malaria, giardiasis, and rheumatic diseases. We find that Quinacrine stabilizes p53 and induces p53-dependent and independent cell death. Treatment by Quinacrine alone at concentrations of 10–20 mM for 1–2 d cannot kill hepatocellular carcinoma cells, such as HepG2, Hep3B, Huh7, which are also resistant to TRAIL. However, Quinacrine renders these cells sensitive to treatment by TRAIL. Co-treatment of these cells with Quinacrine and TRAIL induces overwhelming cell death within 3–4 h. Levels of DR5, a pro-apoptotic death receptor of TRAIL, are increased upon treatment with Quinacrine, while levels of Mcl-1, an anti-apoptotic member of the Bcl-2 family, are decreased. While the synergistic effect of Quinacrine with TRAIL appears to be in part independent of p53, knockdown of p53 in HepG2 cells by siRNA results in more cell death after treatment by Quinacrine and TRAIL. The mechanism by which Quinacrine sensitizes hepatocellular carcinoma cells to TRAIL and ...
Wafik S Eldeiry - One of the best experts on this subject based on the ideXlab platform.
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abstract 3486 synergistic effect of Quinacrine in combination with decitabine for the treatment of acute myeloid leukemia cellsin vitro implication for treatment of aml in the elderly
Cancer Research, 2015Co-Authors: Wenge Wang, David T Dicker, David F Claxton, Hong Gang Wang, Wafik S EldeiryAbstract:Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Demethylating agents remain one of the few options for treatment of AML in the elderly; however, the response rate is limited. In searching for p53 pathway activating agents for cancer therapy, we found that Quinacrine is a potent p53 stimulator and induces tumor cell death. Quinacrine also induces expression of Death Receptor 5 (DR5), reduces expression of anti-apoptotic Mcl-1, and suppresses NFkB activity in tumor cells. Because of its acceptable toxicity profile, history of use in humans, and relevance of the target pathways modulated by Quinacrine we explored whether it may serve as a potent anti-leukemia drug as most leukemia cells carry a wild-type p53. We tested the cytotoxic effects of Quinacrine on malignant hematopoietic cell lines derived from patients with myeloid leukemia, including HL-60, MOLM-13, and MV4-11. We found that Quinacrine induces massive cell death in the cell lines tested, at concentrations from as less as 1 microM to 5 microM, 2-10 times lower than required to induce solid tumor cell death. Most interestingly, Quinacrine facilitates cell death in decitabine pre-treated leukemia cells in a synergistic manner. Further mechanistic studies showed that Quinacrine stabilizes p53, induces Mcl-1 degradation, and PARP cleavage in treated cells. Our work supports translational efforts to advance the use of Quinacrine from the bench to the clinic and provides a preliminary rationale for its combination with decitabine for the treatment of AML. Citation Format: Wenge Wang, David T. Dicker, David F. Claxton, Hong-Gang Wang, Wafik S. El-Deiry. Synergistic effect of Quinacrine in combination with decitabine for the treatment of acute myeloid leukemia cells in vitro : implication for treatment of AML in the elderly. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3486. doi:10.1158/1538-7445.AM2015-3486
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abstract 2527 the drug combination sorafenib and Quinacrine targets the expression of mcl 1 an anti apoptotic protein and candidate prognostic factor in anaplastic thyroid cancer atc
Cancer Research, 2015Co-Authors: Junaid Abdulghani, Prashanth Gokare, Tiffany L Whitcomb, Timothy K Cooper, Jiangang Liao, Jeannicholas Gallant, David M Goldenberg, Niklas Finnberg, Wafik S EldeiryAbstract:Anaplastic thyroid cancer (ATC) is a rare, highly aggressive form of thyroid cancer that frequently is resistant to conventional therapy and therefore requires the development of efficacious novel therapy. Sorafenib, a multi-kinase inhibitor that inhibits the RAF, MEK and ERK kinases, was recently approved by the FDA for late stage metastatic differentiated thyroid cancer but appears to have limited activity in ATC by itself. Sorafenib-based drug combinations with complimentary drug targets are being pursued and evaluated preclinically. However, sorafenib generates a significant number of adverse events in thyroid cancer patients and drug combinations including sorafenib needs to be carefully tailored with respect to toxicity and efficacy. We have previously shown that Quinacrine, a potent small molecule inhibitor of NFKB signaling, combine favorably with several cytotoxic drugs to target hepatocellular and colorectal cancer cells. Quinacrine is an inexpensive drug, has a well established safety profile in human subjects and is being evaluated in cancer clinical trials. Subsequently, we decided to evaluate the efficacy of the drug combination of Quinacrine and sorafenib in ATC. Our combinatorial dose-response modulation of Quinacrine with sorafenib suggests a synergistic drug-drug interaction with respect to growth stasis in a panel of ATC cells in vitro, as defined by Chou-Talalay. Furthermore, in vivo the drug combination of sorafenib and Quinacrine significantly improved survival compared to vehicle control and the current first line chemotherapeutic doxorubicin in a mouse thyroid orthotopic xenograft model of ATC. Dose-escalation toxicity studies in mice suggest that the drug combination was well tolerated and did not trigger synergistic toxicities compared to either drug alone. Significantly less gastrointestinal injury, the most commonly observed toxicity in our study, was present following treatment with the drug combination of sorafenib and Quinacrine compared to treatment with doxorubicin alone. Western blot analysis suggests that the anti-apoptotic Bcl-2 family member Mcl-1 is a target for the drug combination. Indeed, immunohistochemical (IHC) analysis of resected ATC and non-neoplastic thyroid tissues from patients confirmed overexpression of Mcl-1 in ATC indicating target availability. Interestingly, multi-regression analysis of our patient IHC data suggest that high Mcl-1 expression together with tumor size prognosticated poor survival in ATC patients suggesting that Mcl-1 overexpression was linked to a more aggressive tumor behavior. In conclusion, our findings suggest that Quinacrine in combination with sorafenib may be a novel and potentially cost effective therapeutic strategy to target Mcl-1, whose expression potentially may be linked to the disease progression of ATC. Citation Format: Junaid Abdulghani, Jean-Nicholas Gallant, Prashanth Gokare, Timothy Cooper, Tiffany Whitcomb, Jiangang Liao, Jing Liu, David Goldenberg, Niklas K. Finnberg, Wafik S. El-Deiry. The drug combination sorafenib and Quinacrine targets the expression of Mcl-1 - an anti-apoptotic protein and candidate prognostic factor in Anaplastic Thyroid Cancer (ATC). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2527. doi:10.1158/1538-7445.AM2015-2527
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synergistic effect of Quinacrine with chemotherapeutics or trail in hematopoietic malignant cells
Blood, 2014Co-Authors: Wenge Wang, Nathan G Dolloff, David T Dicker, Amriti R Lulla, Liz J Hernandezborrero, Emmanuel K Teye, Mala K Talekar, Wafik S EldeiryAbstract:Abstract Quinacrine is a bioactive acridine derivative which has been used for treatment of malaria, giardiasis, systemic lupus erythematosus, and rheumatoid arthritis. In searching for p53 pathway activating agents for cancer therapy, we found that Quinacrine stabilizes p53 and induces p53-dependent and p53-independent tumor cell death. Quinacrine also induces expression of TRAIL Death Receptor 5 (DR5) and reduces expression of anti-apoptotic Mcl-1 in tumor cells. These activities predict synergies with TRAIL (tumor necrosis factor-related apoptosis inducing ligand) and chemotherapeutic agents in inducing extrinsic and intrinsic pathway mediated apoptosis. In addition, Quinacrine suppresses NFkB activity in tumor cells. Clinical trials have been ongoing for treatment of solid tumors including colon cancer, renal cancer, prostate cancer, and non-small cell lung cancer with Quinacrine in combination with chemotherapy or tyrosine-kinase inhibitors, however, the therapeutic potential of Quinacrine in blood cancer cells has not been established. We tested Quinacrine on hematopoietic malignant cells, which included cell lines of myeloid leukemia, lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, and multiple myeloma. We found that Quinacrine induces massive cell death in the cell lines tested, at concentrations from as less as 1 microM to 5 microM, 2-10 times lower than required to induce solid tumor cell death. Quinacrine synergizes with TRAIL in inducing cell death of TRAIL-sensitive cells and reverses resistance in TRAIL-resistant cells. Quinacrine also synergizes with chemotherapeutic agents, such as antimetabolites, alkylating agents, and tyrosine kinase inhibitors, in inducing apoptosis of hematopoietic cancer cell lines. Our work supports translational efforts to advance the use of Quinacrine from bench to clinic and provides rationale for combination chemotherapeutic regimes for treatment of hematopoietic malignancies. Disclosures No relevant conflicts of interest to declare.
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Quinacrine synergizes with 5 fluorouracil and other therapies in colorectal cancer
Cancer Biology & Therapy, 2011Co-Authors: Jeannicolas Gallant, Wenge Wang, Nathan G Dolloff, Charles D Smith, Joshua E Allen, David T Dicker, Arunasalam Navaraj, Wafik S EldeiryAbstract:Although treatments have improved patient prognosis in surgically resectable colorectal cancer, new effective drugs with improved safety profiles are needed to improve the currently poor outcomes of patients with recurrent or metastatic colorectal cancer. Quinacrine, a small molecule anti-malarial agent that has activity in giardiasis, lupus, prion disease, and used as a means of non-surgical sterilization, has shown cytotoxic activity across a broad range of cancers. Here, we evaluate the potential of adding Quinacrine to anticancer chemotherapeutics and targeted agents as a potential novel combinatorial therapy for advanced colon cancer. We show that Quinacrine synergizes with 5-fluorouracil and significantly enhances the cytotoxicity of sorafenib in a panel of 10 human colorectal cancer cell lines, including those with KRAS mutations protein gel blot analysis confirmed that Quinacrine’s anticancer activity partially arises from its ability to stabilize p53 and lower anti-apoptotic protein levels. In a ...
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abstract 680 Quinacrine sensitizes hepatocellular carcinoma cells to trail via up regulating dr5 and eradicating mcl 1
Cancer Research, 2010Co-Authors: W T Wang, Sharyn I Katz, Junaid Abdulghani, David T Dicker, Wafik S EldeiryAbstract:Quinacrine has been widely explored in treatment of malaria, giardiasis, and rheumatic diseases. We find that Quinacrine stabilizes p53 and induces p53-dependent and independent tumor cell death. Structurally, Quinacrine bears similar characteristics with DNA-intercalating agents. Indeed, Quinacrine competes with Propidium Iodide and shows a high binding affinity to DNA. Interestingly, Quinacrine is a fluorescent dye that can be visualized under a laser microscope. In live cells, Quinacrine is mainly clustered in the cytoplasm with a faint fluorescent signal in the nucleus. If the cells are fixed with methanol, Quinacrine accumulates predominantly in the nucleus. Treatment by Quinacrine alone at concentrations of 10-20 μM for 1-2 days can not kill hepatocellular carcinoma cells, such as HepG2, Hep3B, Huh7, which are also resistant to TRAIL. However, Quinacrine renders these cells sensitive to treatment of TRAIL significantly. Co-treatment of these cells with Quinacrine and TRAIL induces overwhelming cell death in 3-4 hr. Western blotting shows the level of DR5, a pro-apoptotic death receptor of TRAIL, is increased while MCL-1, a member of the Bcl-2 family, is decreased. While the synergistic effect of Quinacrine with TRAIL appears to be in part independent of p53, knockdown of p53 in HepG2 cells by siRNA results in more cell death after treatment by Quinacrine and TRAIL. The mechanism of Quinacrine sensitization of hepatocellular carcinoma cells and the potential for clinical application are being further explored. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 680.
David C Sokal - One of the best experts on this subject based on the ideXlab platform.
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Quinacrine sterilization and gynecologic cancers a case control study in northern vietnam
Epidemiology, 2010Co-Authors: David C Sokal, Kavita Nanda, Debra H Weiner, Trinh Huu Vach, Margaret F Mccann, Claude Drobnes, Mana Rochanawutanon, Nguyen Ba Duc, Nguyen Dinh LoanAbstract:BACKGROUND: Over 100000 women worldwide have been sterilized by insertion of Quinacrine into the uterus to induce tubal scarring. Concern has been expressed about possible carcinogenicity and specifically the risk of uterine cancer. METHODS: From 2001 through 2006 we conducted a population-based case-control study of gynecologic cancers in 12 provinces in northern Vietnam where relatively large numbers of women had received Quinacrine. Cases of incident cervical ovarian and uterine cancer were identified at provincial hospitals or at referral hospitals in Hanoi. For each case 3 age- and residence-matched controls were randomly selected from the population registries of the cases home community. RESULTS: The prevalence of Quinacrine exposure was 1.2% among cases and 1.1% among controls. For cervical cancer analysis of 606 cases (9 exposed) and their 1774 matched controls (18 exposed) produced an odds ratio of 1.44 (95% confidence interval = 0.59-3.48) (adjusted for several covariates including human papillomavirus risk score). For ovarian cancer based on 262 cases (3 exposed) and 755 controls (8 exposed) and adjusted for age and number of years of ovulation the odds ratio was 1.26 (0.21-5.45). For uterine cancer none of the cases-including 23 cases of leiomyosarcoma-was exposed to Quinacrine. The 95% confidence interval based on 161 cases (none exposed) and 470 controls (7 exposed) and adjusted only for age was 0-1.85. CONCLUSION: We found no evidence of a relationship between Quinacrine sterilization and gynecologic cancer.
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contraceptive effectiveness of two insertions of Quinacrine results from 10 year follow up in vietnam
Contraception, 2008Co-Authors: David C Sokal, Do Trong Hieu, Nguyen Dinh Loan, David Hubacher, Kavita Nanda, Debra H Weiner, Trinh Huu VachAbstract:Abstract Background This study was conducted to evaluate the long-term effectiveness of two insertions of Quinacrine pellets for nonsurgical sterilization among women in northern Vietnam. Study Design Observational cohort study of 1335 women who received two Quinacrine insertions between 1989 and 1993. Results About 90% of the study population participated in the last round of interviews. Cumulative follow-up time for this cohort was 14,294 person-years. The 1-, 5- and 10-year cumulative pregnancy probabilities for Quinacrine were 3.3% (95% CI, 2.4–4.3), 10.0% (95% CI, 8.4–11.6) and 12.1% (95% CI, 10.4–13.9), respectively. Pregnancy estimates with Quinacrine in this cohort were higher than that reported from US-based research on surgical tubal sterilization and higher than results of Quinacrine sterilization in Chile. Quinacrine effectiveness was better among older women. Conclusion The effectiveness of Quinacrine in Vietnam was lower than other forms of sterilization. Factors such as inconsistent training and use of various insertion techniques may have contributed to the relatively high failure rate.
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safety of Quinacrine contraceptive pellets results from 10 year follow up in vietnam
Contraception, 2008Co-Authors: David C Sokal, Do Trong Hieu, Nguyen Dinh Loan, David Hubacher, Kavita Nanda, Debra H Weiner, Trinh Huu VachAbstract:Abstract Background This study was conducted to evaluate long-term safety of Quinacrine pellets for nonsurgical sterilization among women in Vietnam. Study Design Observational cohort study of 2735 women who had Quinacrine insertions between 1989 and 1993 compared to 1623 women who received an intrauterine device (IUD). Results Cumulative follow-up times for the Quinacrine and IUD cohorts were 28,697 and 17,382 person-years, respectively, and losses to follow-up were 6% and 7%, respectively. Quinacrine users had a higher incidence of ectopic pregnancy compared to IUD users (risk ratio, 2.2; 95% confidence interval, 1.06–4.54); the risks of cancer, hysterectomy, pelvic/gynecologic surgery and death were similar in the two groups. Two Quinacrine insertions appeared to lower the risk of ectopic pregnancy to that of surgical tubal occlusion. Conclusions Use of Quinacrine in this cohort appeared to have minimal health risks. Other research, including preclinical studies, needs to be considered in an overall evaluation of whether the combination of safety and efficacy provide a basis for Quinacrine's approval by appropriate regulatory agencies.
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cancer risk among women sterilized with transcervical Quinacrine in chile an update through 1996
Fertility and Sterility, 2000Co-Authors: David C Sokal, J. Zipper, Alfredo Dabancens, Rene GuzmanseraniAbstract:Abstract Objective: To determine whether further follow-up of a cohort of Chilean women would demonstrate an increased risk of invasive cancer associated with Quinacrine sterilization. Design: Cohort study. Cancer cases were evaluated using cohort analyses. Setting: Santiago and Valdivia, Chile Subject(s): Fourteen hundred ninety-two women who received transcervical Quinacrine pellets for contraceptive sterilization between l977 and l989. Method(s): Interviews and reviews of medical records. Main Outcome Measure(s): Age- and site-specific incidence of invasive cancers. Result(s): During 13,444 person-years of follow-up, 25 invasive cancers were identified, including 8 new cases. This compares with 21.9 expected cancers, based on age-specific rates from the Cali, Colombia, cancer registry. Eight cases of cervical cancer were observed, compared with the 6.3 expected. Since the initial study’s confirmation of a single case of leiomyosarcoma, no other noncervical uterine cancers have been diagnosed. The number of observed person-years gives an expectation of 0.62 noncervical uterine cancers. One case of ovarian cancer was diagnosed, compared with the 0.99 expected. Conclusion(s): Rates of cancer among women exposed to intrauterine Quinacrine are not significantly different from population-based rates.
Jeannicolas Gallant - One of the best experts on this subject based on the ideXlab platform.
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first in human phase 1b trial of Quinacrine plus capecitabine in patients with refractory metastatic colorectal cancer
Clinical Colorectal Cancer, 2021Co-Authors: Arthur Winer, Jeannicolas Gallant, Crystal S Denlinger, Namrata Vijayvergia, Steven J Cohen, Igor Astaturov, Efrat Dotan, Edward W Wang, Miriam Kunkel, Bora LimAbstract:Abstract Background Quinacrine plus a fluoropyrimidine has in vivo efficacy against metastatic colorectal cancer (mCRC). This phase 1b trial evaluated the combination of Quinacrine plus capecitabine in patients with treatment-refractory mCRC. Patients and Methods Using a modified Simon accelerated titration design, adults with treatment-refractory mCRC were treated with capecitabine 1000 mg/m2 twice daily for 14/21-day cycle, and escalating doses of Quinacrine 100 mg daily, 100 mg twice daily, and 200 mg twice daily for 21 days. The primary endpoint was identifying the maximum tolerated dose, determining tolerability and safety. In an expansion cohort, it was overall response rate and time to tumor progression (TTP). Results Ten patients (median age of 60 years) were treated in phase 1b. The first 2 Quinacrine dosing levels were well tolerated. Dose-limiting toxicities were seen in 3 patients treated with Quinacrine 200 mg twice daily. Five additional patients tolerated Quinacrine 100 mg twice daily without further dose-limiting toxicities, thus establishing the maximum tolerated dose. Seven additional expansion-cohort patients enrolled onto the study before Quinacrine manufacturing ceased within the United States. Five patients experienced stable disease, 1 partial response, and 10 disease progression. Median TTP overall was 2.12 months and median overall survival 5.22 months for the 17 patients. Conclusion Capecitabine and Quinacrine can be safely administered at the maximum tolerated dose of capecitabine 1000 mg/m2 by mouth twice daily on days 1-14 and Quinacrine 100 mg by mouth twice daily on days 1-21 of a 21-day cycle in mCRC patients. Although the expansion study was halted early, TTP was in line with other studies of refractory mCRC, suggesting activity of this regimen in heavily pretreated patients.
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a phase ib trial to evaluate the safety and efficacy of Quinacrine plus capecitabine in patients with refractory metastatic colorectal cancer
Journal of Clinical Oncology, 2019Co-Authors: Arthur Winer, Jeannicolas Gallant, Crystal S Denlinger, Namrata Vijayvergia, Steven J Cohen, Efrat Dotan, Edward W Wang, Miriam Kunkel, Igor Astsaturov, Bora LimAbstract:e15020Background: Acridines emerged from a cell-based screen for p53-pathway restoring compounds. Quinacrine, an acridine demonstrating p53 pathway restoration properties, displayed preclinical ant...
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sorafenib and Quinacrine target anti apoptotic protein mcl1 a poor prognostic marker in anaplastic thyroid cancer atc
Clinical Cancer Research, 2016Co-Authors: Jeannicolas Gallant, Junaid Abdulghani, David T Dicker, Prashanth Gokare, Tiffany L Whitcomb, Timothy K Cooper, Jiangang LiaoAbstract:Purpose: Anaplastic thyroid cancer (ATC) comprises ~2% of all thyroid cancers and its median survival rate remains poor. It is responsible for more than one-third of thyroid cancer-related deaths. ATC is frequently resistant to conventional therapy and NFkappaB-signaling has been proposed to be a feature of the disease. We aimed to assess the activity of the anti-malaria drug Quinacrine known to target NFkappaB-signaling in combination with the clinically relevant kinase inhibitor sorafenib in ATC cells. The presence of NFkappaB-p65/RelA and its target Mcl-1 was demonstrated in ATC by meta-data gene set enrichment analysis and immunohistochemistry (IHC). We assessed the responses of a panel of human ATC cell lines to Quinacrine and sorafenib in vitro and in vivo. Results: We detected increased expression of NFkappaB-p65/RelA and Mcl-1 in the nucleus of a subset of ATC compared to non-neoplastic thyroid. ATC-cells were found to respond with additive/synergistic tumor cell-killing to the combination of sorafenib plus Quinacrine in vitro and the drug combination improves survival of immunodeficient mice injected orthotopically with ATC-cells as compared to mice administered either compound alone or doxorubicin. We also demonstrate that the combination of sorafenib and Quinacrine is well tolerated in mice. At the molecular level, Quinacrine and sorafenib inhibited expression of the pro-survival gene Mcl-1, pStat3 and dampened NFkappaB signaling. Conclusion: The combination of Quinacrine and sorafenib targets emerging molecular hallmarks of ATC and shows promising results in clinically relevant models for the disease. Further testing of sorafenib plus Quinacrine can be conducted in ATC patients.
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sorafenib and Quinacrine target anti apoptotic protein mcl1 a poor prognostic marker in anaplastic thyroid cancer atc
Clinical Cancer Research, 2016Co-Authors: Jeannicolas Gallant, Junaid Abdulghani, David T Dicker, Prashanth Gokare, Tiffany L Whitcomb, Timothy K Cooper, Jiangang LiaoAbstract:Purpose and Experimental Design: Anaplastic thyroid cancer (ATC) comprises approximately 2% of all thyroid cancers, and its median survival rate remains poor. It is responsible for more than one third of thyroid cancer–related deaths. ATC is frequently resistant to conventional therapy, and NFκB signaling has been proposed to be a feature of the disease. We aimed to assess the activity of the antimalaria drug Quinacrine known to target NFκB signaling in combination with the clinically relevant kinase inhibitor sorafenib in ATC cells. The presence of NFκB-p65/RELA and its target MCL1 was demonstrated in ATC by meta-data gene set enrichment analysis and IHC. We assessed the responses of a panel of human ATC cell lines to Quinacrine and sorafenib in vitro and in vivo. Results: We detected increased expression of NFκB-p65/RELA and MCL1 in the nucleus of a subset of ATC compared with non-neoplastic thyroid. ATC cells were found to respond with additive/synergistic tumor cell killing to the combination of sorafenib plus Quinacrine in vitro, and the drug combination improves survival of immunodeficient mice injected orthotopically with ATC cells as compared with mice administered either compound alone or doxorubicin. We also demonstrate that the combination of sorafenib and Quinacrine is well tolerated in mice. At the molecular level, Quinacrine and sorafenib inhibited expression of prosurvival MCL1, pSTAT3, and dampened NFκB signaling. Conclusions: The combination of Quinacrine and sorafenib targets emerging molecular hallmarks of ATC and shows promising results in clinically relevant models for the disease. Further testing of sorafenib plus Quinacrine can be conducted in ATC patients. Clin Cancer Res; 22(24); 6192–203. ©2016 AACR.
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Quinacrine sensitizes hepatocellular carcinoma cells to trail and chemotherapeutic agents
Cancer Biology & Therapy, 2011Co-Authors: Wenge Wang, Jeannicolas Gallant, Sharyn I Katz, Nathan G Dolloff, Charles D Smith, Junaid Abdulghani, Joshua E Allen, David T DickerAbstract:Quinacrine has been widely explored in treatment of malaria, giardiasis, and rheumatic diseases. We find that Quinacrine stabilizes p53 and induces p53-dependent and independent cell death. Treatment by Quinacrine alone at concentrations of 10–20 mM for 1–2 d cannot kill hepatocellular carcinoma cells, such as HepG2, Hep3B, Huh7, which are also resistant to TRAIL. However, Quinacrine renders these cells sensitive to treatment by TRAIL. Co-treatment of these cells with Quinacrine and TRAIL induces overwhelming cell death within 3–4 h. Levels of DR5, a pro-apoptotic death receptor of TRAIL, are increased upon treatment with Quinacrine, while levels of Mcl-1, an anti-apoptotic member of the Bcl-2 family, are decreased. While the synergistic effect of Quinacrine with TRAIL appears to be in part independent of p53, knockdown of p53 in HepG2 cells by siRNA results in more cell death after treatment by Quinacrine and TRAIL. The mechanism by which Quinacrine sensitizes hepatocellular carcinoma cells to TRAIL and ...
