FLLL12 induces apoptosis in lung cancer cells through a p53/p73-independent but death receptor 5-dependent pathway

Abstract

Unlike chemotherapy drugs, the safety of natural compounds such as curcumin has been well established. However, the potential use of curcumin in cancer has been compromised by its low bioavailability, limited tissue distribution and rapid biotransformation leading to low in vivo efficacy. To circumvent these problems, more potent and bioavailable analogs have been synthesized. In the current study, we investigated the mechanism of anti-tumor effect of one such analog, FLLL12, in lung cancers. IC50 values measured by sulforhodamine B (SRB) assay at 72 h and apoptosis assays (annexin V staining, cleavage of PARP and caspase-3) suggest that FLLL12 is 5–10-fold more potent than curcumin against a panel of premalignant and malignant lung cancer cell lines, depending on the cell line. Moreover, FLLL12 induced the expression of death receptor-5 (DR5). Ablation of the expression of the components of the extrinsic apoptotic pathway (DR5, caspase-8 and Bid) by siRNA significantly protected cells from FLLL12-induced apoptosis (p < 0.05). Analysis of mRNA expression revealed that FLLL-12 had no significant effect on the expression of DR5 mRNA expression. Interestingly, inhibition of global phosphatase activity as well as protein tyrosine phosphatases (PTPs), but not of alkaline phosphatases, strongly inhibited DR5 expression and significantly inhibited apoptosis (p < 0.05), suggesting the involvement of PTPs in the regulation of DR5 expression and apoptosis. We further showed that the apoptosis is independent of p53 and p73. Taken together, our results strongly suggest that FLLL12 induces apoptosis of lung cancer cell lines by post-transcriptional regulation of DR5 through activation of protein tyrosine phosphatase(s).

Apoptosis Activation in Human Lung Cancer Cell Lines by a Novel Synthetic Peptide Derived from Conus californicus Venom

“…Despite all efforts to advance surgical procedures, radiotherapy and chemotherapy, the five-year survival rate for lung cancer patients has remained almost constant over the past three decades and persists at a dismal 15% [ 3 , 4 ]. Thus, there is an increasing emphasis on strategies to maximize tumor control, prolong survival, minimize chemotherapy side effects and improve quality of life for patients [ 5 ].…”

“…Deregulation of apoptosis either by loss of pro-apoptotic signals or by gain of anti-apoptotic signals can lead to initiation, promotion and progression of cancer, and it may also result in therapy failure [ 24 ]. Successful elimination of cancer cells from the body depends on activation of cell death by apoptosis, thus developing peptides to stimulate caspase activation and apoptosis execution represent a promising strategy to develop cancer chemotherapeutics [ 5 ].…”

Preclinical In Vitro, In Vivo, and Pharmacokinetic Evaluations of FLLL12 for the Prevention and Treatment of Head and Neck Cancers

“…Although the antitumor effects of FLLL12 have been investigated in prostate, breast, pancreatic, lung and colon cancer cell lines and compared with those of curcumin (13, 21–23), the agent has never been tested in SCCHN cell lines. In order to explore the mechanism of anti-tumor effect of FLLL12 in SCCHN, we first assessed the sensitivity of different premalignant (MSK-LEUK1) and malignant SCCHN cell lines to FLLL12 versus curcumin by comparing IC 50 values measured using SRB assays at 72 h. As shown in Table 1, depending on the cell line, the IC 50 values of FLLL12 ranged from 0.35–1.55 µM, compared with 4.53–17.42 µM for curcumin.…”

“…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, 21–23). FLLL12 induces apoptosis of these cancer cells by inhibition of two major survival pathways, AKT and STAT3 or inducing DR5 expression.…”

Cancer Chemoprevention by Phytochemicals: Nature’s Healing Touch

“…It also remains one of the most extensively modified phytochemicals, with so many reported analogs that it will be beyond the scope of this article to comment on every single curcumin analog that has been tested and reported for its enhanced anticancer activity. Just to put this into perspective, some curcumin analogs ( Table 3 ) reported within the past two years include C-150 (inhibits NF-κB in glioblastoma cells [ 123 ]), Da0324 (inhibits NF-κB in gastric cancer cells [ 124 ]), 2,2’-fluoromonocarbonyl analog (modulates ROS in lung cancer cells [ 125 ]), A17 (induces ER stress in lung cancer cells [ 126 ]), MC37 (induces cell cycle arrest in colorectal cancer cells [ 127 ]), HO-3867 (STAT3 inhibitor in pancreatic cancer cells [ 128 ]), BDMC-A (inhibits NF-κB in breast cancer cells [ 129 ]), GO-Y078 (inhibits invasion of endothelial cells [ 130 ]), DM-1 (induces apoptosis in melanoma cells [ 131 ]), FLLL12 (induces apoptosis in lung cancer cells [ 132 ]), BHBA (activates Nrf2 in lung cancer models [ 133 ]) and L49H37 (induces apoptosis in pancreatic stellate cells [ 134 ]). Other than these, there are a few other curcumin analogs that have been investigated in comparatively more detail.…”