PCI-13, UM-22B and JHU022 cell lines were procured from Dr. is usually significantly more potent and has more favorable pharmacokinetic properties than curcumin. FLLL12 strongly inhibited the expression of p-EGFR, EGFR, p-AKT, AKT, Bcl-2 and Bid and increased the expression of Bim. Overexpression of constitutively active AKT or Bcl-2 or ablation of Bim or Bid significantly Rabbit Polyclonal to ELAV2/4 inhibited FLLL12-induced apoptosis. Further mechanistic studies revealed that FLLL12 regulated EGFR and AKT at transcriptional levels, whereas Bcl-2 was regulated at the translational level. Finally, FLLL12 strongly inhibited the AKT downstream targets mTOR and FOXO1a and 3a. Taken together, our results strongly suggest that FLLL12 is usually a potent curcumin analog with more favorable pharmacokinetic properties that induces apoptosis of head and neck malignancy cell lines by inhibition of survival proteins including EGFR, AKT and Bcl-2 and increasing of the pro-apoptotic protein Bim. and interferes with multiple oncogenic and tumor suppressor pathways, its clinical application is usually severely compromised by its poor absorption, low bioavailability, rapid biotransformation and low potency (5, 6). To circumvent these issues, approaches such as the synthesis of more potent and bioavailable analogs and the modification of delivery systems have been extensively considered. The -diketone moiety is responsible for the instability and poor pharmacokinetic profile of curcumin. Structural modifications of the aryl side chains or diketone moiety have significantly improved solubility, stability, and bioavailability (7). More than a thousand monocarbonyl analogs of curcumin have been synthesized and tested and for their anti-cancer effects. Many of these compounds show 10C20Cfold more potency than curcumin, have better pharmacokinetic properties and VU6005649 effectively inhibit xenograft growth (8). GO-Y078, 079, 030, 097, and 098 comprise a group of analogs that are more soluble in water and are at least 10-fold more potent than natural curcumin (9). Several members of the EF-series of curcumin analogs, including EF24, 31 and UBS109, synthesized by modifying the diketo chain showed ~10-fold better anti-cancer efficacy than natural curcumin and inhibited tumor growth in xenograft models (10C12). Many members of the FLLL-series of analogs synthesized by modifying the aryl side chain also exhibited higher anti-growth efficacy and selectivity for cancer cells sparing normal cells (13, 14). FLLL32 also significantly inhibited breast malignancy xenograft growth in nude mice (15). Dimethoxycurcumin exhibited significantly higher stability and against microsomal metabolism (16). PAC, another synthetic curcumin analog, showed higher stability in blood and greater biodistribution and bioavailability than curcumin in mice and is more water soluble (17). The compound is also more potent in inducing apoptosis. FH Sarkars group has synthesized a series of curcumin analogs and evaluated their effects against colon and pancreatic cancer cells (18). The group has identified VU6005649 a compound known as CDF with superior anti-cancer activity in colon, prostate and pancreatic cancer cell lines that exhibited 2.7-fold greater systemic drug level and 10.6-fold higher accumulation in pancreatic tissue than curcumin (19). Vyas et al. and Park et al. have comprehensively reviewed curcumin analogs with improved efficacy and bioavailability (5, 7). In the current study, we investigated the pharmacokinetic properties, the and anti-tumor efficacy, and the mechanism of apoptosis induced by FLLL12 in squamous cell carcinoma of the head and neck (SCCHN). SCCHN is the 6th most common cancer in the US and represents ~3% of all cancer cases, with an estimated 59,000 new cases and 12,000 deaths in 2014 (20). FLLL12 is usually a synthetic curcumin analog synthesized by modifying the aryl side chains to circumvent the efficacy, selectivity and bioavailability issues associated with natural compounds. FLLL12 is usually ~10-fold VU6005649 more potent than natural curcumin against breast, prostate, colorectal, pancreatic and lung cancer cell lines and possesses selective activity against cancer cells (13, 21C23). FLLL12 induces apoptosis of these cancer cells by inhibition of two major survival pathways, AKT and STAT3 or.FLLL12 induces apoptosis of these cancer cells by inhibition of two major survival pathways, AKT and STAT3 or inducing DR5 expression. level. Finally, FLLL12 strongly inhibited the AKT downstream targets mTOR and FOXO1a and 3a. Taken together, our results strongly suggest that FLLL12 is a potent curcumin analog with more favorable pharmacokinetic properties that induces apoptosis of head and neck cancer cell lines by inhibition of survival proteins including EGFR, AKT and Bcl-2 and increasing of the pro-apoptotic protein Bim. and interferes with multiple oncogenic and tumor suppressor pathways, its clinical application is severely compromised by its poor absorption, low bioavailability, rapid biotransformation and low potency (5, 6). To circumvent these issues, approaches such as the synthesis of more potent and bioavailable analogs and the modification of delivery systems have been extensively considered. The -diketone moiety is responsible for the instability and weak pharmacokinetic profile of curcumin. Structural modifications of the aryl side chains or diketone moiety have significantly improved solubility, stability, and bioavailability (7). More than a thousand monocarbonyl analogs of curcumin have been synthesized and tested and for their anti-cancer effects. Many of these compounds show 10C20Cfold more potency than curcumin, have better pharmacokinetic properties and effectively inhibit xenograft growth (8). GO-Y078, 079, 030, 097, and 098 comprise a group of analogs that are more soluble in water and are at least 10-fold more potent than natural curcumin (9). Several members of the EF-series of curcumin analogs, including EF24, 31 and UBS109, synthesized by modifying the diketo chain showed ~10-fold better anti-cancer efficacy than natural curcumin and inhibited tumor growth in xenograft models (10C12). Many members of the FLLL-series of analogs synthesized by modifying the aryl side chain also exhibited higher anti-growth efficacy and selectivity for cancer cells sparing normal cells (13, 14). FLLL32 also significantly inhibited breast cancer xenograft growth in nude mice (15). Dimethoxycurcumin exhibited significantly higher stability and against microsomal metabolism (16). PAC, another synthetic curcumin analog, showed higher stability in blood and greater biodistribution and bioavailability than curcumin in mice and is more water soluble (17). The compound is also more potent in inducing apoptosis. FH Sarkars group has synthesized a series of curcumin analogs and evaluated their effects against colon and pancreatic cancer cells (18). The group has identified a compound known as CDF with superior anti-cancer activity in colon, prostate and pancreatic cancer cell lines that exhibited 2.7-fold greater systemic drug level and 10.6-fold higher accumulation in pancreatic tissue than curcumin (19). Vyas et al. and Park et al. have comprehensively reviewed curcumin analogs with improved efficacy and bioavailability (5, 7). In the current study, we investigated the pharmacokinetic properties, the and anti-tumor efficacy, and the mechanism of apoptosis induced by FLLL12 in squamous cell carcinoma of the head and neck (SCCHN). SCCHN is the 6th most common cancer in the US and represents ~3% of all cancer cases, with an estimated 59,000 new cases and 12,000 deaths in 2014 (20). FLLL12 is a synthetic curcumin analog synthesized by modifying the aryl side chains to circumvent the efficacy, selectivity and bioavailability issues associated with natural compounds. FLLL12 is ~10-fold more potent than natural curcumin against breast, prostate, colorectal, pancreatic and lung cancer cell lines and possesses selective activity against cancer cells (13, 21C23). FLLL12 induces apoptosis of these cancer cells by inhibition of two major survival pathways, AKT and STAT3 or inducing DR5 expression. However, the detailed mechanisms underlying FLLL12-induced apoptosis are not fully understood. Moreover, FLLL12 has never been tested or against SCCHN cancer cell lines. The pharmacokinetic (PK) properties of FLLL12 are also unknown. In the present study, for the first time, we showed that depending on the cell line, FLLL12 is 10C24Cfold more potent than curcumin and induces apoptosis in SCCHN cell lines Moreover, we demonstrated that FLLL12 induces apoptosis in.FLLL12 induces apoptosis of these cancer cells by inhibition of two major survival pathways, AKT and STAT3 or inducing DR5 expression. of Bim or Bid significantly VU6005649 inhibited FLLL12-induced apoptosis. Further mechanistic studies revealed that FLLL12 regulated EGFR and AKT at transcriptional levels, whereas Bcl-2 was regulated at the translational level. Finally, FLLL12 strongly inhibited the AKT downstream targets mTOR and FOXO1a and 3a. Taken together, our results strongly suggest that FLLL12 is a potent curcumin analog with more favorable pharmacokinetic properties that induces apoptosis of head and neck tumor cell lines by inhibition of survival proteins including EGFR, AKT and Bcl-2 and increasing of the pro-apoptotic protein Bim. and interferes with multiple oncogenic and tumor suppressor pathways, its medical application is definitely severely jeopardized by its poor absorption, low bioavailability, quick biotransformation and low potency (5, 6). To circumvent these issues, approaches such as the synthesis of more potent and bioavailable analogs and the changes of delivery systems have been extensively regarded as. The -diketone moiety is responsible for the instability and fragile pharmacokinetic profile of curcumin. Structural modifications of the aryl part chains or diketone moiety have significantly improved solubility, stability, and bioavailability (7). More than a thousand monocarbonyl analogs of curcumin have been synthesized and tested and for his or her anti-cancer effects. Many of these compounds display 10C20Cfold more potency than curcumin, have better pharmacokinetic properties and efficiently inhibit xenograft growth (8). GO-Y078, 079, 030, 097, and 098 comprise a group of analogs that are more soluble in water and are at least 10-collapse more potent than natural curcumin (9). Several members of the EF-series of curcumin analogs, including EF24, 31 and UBS109, synthesized by modifying the diketo chain showed ~10-collapse better anti-cancer effectiveness than natural curcumin and inhibited tumor growth in xenograft models (10C12). Many users of the FLLL-series of analogs synthesized by modifying the aryl part chain also exhibited higher anti-growth effectiveness and selectivity for malignancy cells sparing normal cells (13, 14). FLLL32 also significantly inhibited breast tumor xenograft growth in nude mice (15). Dimethoxycurcumin exhibited significantly higher stability and against microsomal rate of metabolism (16). PAC, another synthetic curcumin analog, showed higher stability in blood and higher biodistribution and bioavailability than curcumin in mice and is more water soluble (17). The compound is also more potent in inducing apoptosis. FH Sarkars group offers synthesized a series of curcumin analogs and evaluated their effects against colon and pancreatic malignancy cells (18). The group offers identified a compound known as CDF with superior anti-cancer activity in colon, prostate and pancreatic malignancy cell lines that exhibited 2.7-fold higher systemic drug level and 10.6-fold higher accumulation in pancreatic cells than curcumin (19). Vyas et al. and Park et al. have comprehensively examined curcumin analogs with improved effectiveness and bioavailability (5, 7). In the current study, we investigated the pharmacokinetic properties, the and anti-tumor effectiveness, and the mechanism of apoptosis induced by FLLL12 in squamous cell carcinoma of the head and neck (SCCHN). SCCHN is the 6th most common cancer in the US and represents ~3% of all cancer instances, with an estimated 59,000 fresh instances and 12,000 deaths in 2014 (20). FLLL12 is definitely a synthetic curcumin analog synthesized by modifying the aryl part chains to circumvent the effectiveness, selectivity and bioavailability issues associated with natural compounds. FLLL12 is definitely ~10-collapse more potent than natural curcumin against breast, prostate, colorectal, pancreatic and lung malignancy cell lines and possesses selective activity against malignancy cells (13, 21C23). FLLL12 induces.Eighteen woman nude mice (athymic After adaptation for a few days in the new environment, the mice were subcutaneously injected with 4106 Tu686 cells into the ideal flank. Finally, FLLL12 strongly inhibited the AKT downstream focuses on mTOR and FOXO1a and 3a. Taken together, our results strongly suggest that FLLL12 is definitely a potent curcumin analog with more beneficial pharmacokinetic properties that induces apoptosis of head and neck tumor cell lines by inhibition of survival proteins including EGFR, AKT and Bcl-2 and increasing of the pro-apoptotic protein Bim. and interferes with multiple oncogenic and tumor suppressor pathways, its medical application is definitely severely jeopardized by its poor absorption, low bioavailability, quick biotransformation and low potency (5, 6). To circumvent these issues, approaches such as the synthesis of more potent and bioavailable analogs and the changes of delivery systems have been extensively regarded as. The -diketone moiety is responsible for the instability and fragile pharmacokinetic profile of curcumin. Structural modifications of the aryl part chains or diketone moiety have significantly improved solubility, stability, and bioavailability (7). More than a thousand monocarbonyl analogs of curcumin have been synthesized and tested and for his or her anti-cancer effects. Many of these compounds display 10C20Cfold more potency than curcumin, have better pharmacokinetic properties and efficiently inhibit xenograft growth (8). GO-Y078, 079, 030, 097, and 098 comprise a group of analogs that are more soluble in water and are at least 10-collapse more potent than natural curcumin (9). Several members of the EF-series of curcumin analogs, including EF24, 31 and UBS109, synthesized by modifying the diketo chain showed ~10-collapse better anti-cancer effectiveness than natural curcumin and inhibited tumor growth in xenograft models (10C12). Many users of the FLLL-series of analogs synthesized by modifying the aryl part chain also exhibited higher anti-growth effectiveness and selectivity for malignancy cells sparing normal cells (13, 14). FLLL32 also significantly inhibited breast tumor xenograft growth in nude mice (15). Dimethoxycurcumin exhibited significantly higher stability and against microsomal rate of metabolism (16). PAC, another synthetic curcumin analog, showed higher stability in blood and higher biodistribution and bioavailability than curcumin in mice and is more water soluble (17). The compound is also more potent in inducing apoptosis. FH Sarkars group offers synthesized a series of curcumin analogs and evaluated their effects against colon and pancreatic malignancy cells (18). The group offers identified a compound known as CDF with superior anti-cancer activity in colon, prostate and pancreatic malignancy cell lines that exhibited 2.7-fold higher systemic drug level and 10.6-fold higher accumulation in pancreatic tissue than curcumin (19). Vyas et al. and Park et al. have comprehensively reviewed curcumin analogs with improved efficacy and bioavailability (5, 7). In the current study, we investigated the pharmacokinetic properties, the and anti-tumor efficacy, and the mechanism of apoptosis induced by FLLL12 in squamous cell carcinoma of the head and neck (SCCHN). SCCHN is the 6th most common cancer in the US and represents ~3% of all cancer cases, with an estimated 59,000 new cases and 12,000 deaths in 2014 (20). FLLL12 is usually a synthetic curcumin analog synthesized by modifying the aryl side chains to circumvent the efficacy, selectivity and bioavailability issues associated with natural compounds. FLLL12 is usually ~10-fold more potent than natural curcumin against breast, prostate, colorectal, pancreatic and lung cancer cell lines and possesses selective activity against cancer cells (13, 21C23). FLLL12 induces apoptosis of these malignancy cells by inhibition of two major survival pathways, AKT and STAT3 or inducing DR5 expression. However, the detailed mechanisms underlying FLLL12-induced apoptosis are not fully understood. Moreover, FLLL12 has never been tested or against SCCHN cancer cell lines. The pharmacokinetic (PK) properties of FLLL12 are also unknown. In the present study, for the.
