The novel tankyrase inhibitor (AZ1366) enhances irinotecan activity in tumors that exhibit elevated tankyrase and irinotecan resistance

Quackenbush, Kevin S.; Bagby, Stacey M.; Tai, Wai Meng David; Messersmith, Wells A.; Schreiber, Anna; Greene, Justin M.; Kim, Jihye; Wang, Guoliang; Purkey, Alicia; Pitts, Todd M.; Nguyen, Anna; Gao, Dexiang; Blatchford, Patrick J.; Capasso, Anna; Schuller, Alwin G.; Eckhardt, S. Gail; Arcaroli, John J.

doi:10.18632/oncotarget.8626

Cited by 35 publications

(30 citation statements)

References 36 publications

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“…Although it seems that MK1775 monotherapy could achieve an anticancer effect in p53 mutant colonic cancer cells, the dosage for treatment is still a challenge, as the toxicity of agents targeting the cell cycle checkpoint is big problem. Combination with other chemotherapy drugs is a better choice as a first-line chemotherapy regime in metastatic colonic cancer (25), and a number of studies are seeking the proper strategy to increase the sensitivity of cancer cells to the cytotoxicity effect (26)(27)(28). In the present study MK1775 was demonstrated to increase the sensitivity of cells to the effect of irinotecan both in HT29 and SW480, and resulting in increased γ-H2AX and cleaved-caspase 3.…”

Section: Discussionmentioning

confidence: 52%

Wee1 inhibition can suppress tumor proliferation and sensitize p53 mutant colonic cancer cells to the anticancer effect of irinotecan

et al. 2017

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Wee1 is an oncogenic nuclear kinase, which can regulate the cell cycle as a crucial G2M checkpoint. Overexpression of Wee1 can be observed in various cancer types, which may lead to a poor prognosis, but the potential therapeutic value of Wee1 in colorectal cancer has not been fully studied. In the present study, the role of Wee1 in colonic cancer was investigated. Wee1 inhibition by small interfering RNA was demonstrated to significantly restrain cancer cell proliferation and sensitize the p53 mutant colonic cancer cell lines HT29 and SW480 to the effect of treatment with ionizing radiation. The anticancer effect of the Wee1 inhibitor MK1775 was investigated in these two colonic cancer cell lines. MK1775 was demonstrated to induce significant DNA damage, suppress cell viability and induce apoptosis. In addition, MK1775 sensitized HT29 and SW480 cells to the effect of irinotecan. Annexin V/propidium iodide staining demonstrated that combination therapy can induce increased apoptosis compared with MK1775 or irinotecan monotherapy. The results of western blot analysis also indicated increased expression of the DNA damage marker histone H2AX, and apoptosis‑associated protein cleaved caspase 3, in HT29 and SW480 cells. In conclusion, the present study indicated that Wee1 may be a valuable target for treatment of p53 mutant colonic cancer.

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Section: Discussionmentioning

confidence: 52%

Wee1 inhibition can suppress tumor proliferation and sensitize p53 mutant colonic cancer cells to the anticancer effect of irinotecan

et al. 2017

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“…The TNKS1/2 enzymes regulate Axin2 degradation by PARylation, a mechanism which was elucidated in Huang et al (2009). Results from recently developed TNKS1/2 inhibitors have shown stabilization of Axin2 protein, decrease in Axin2 mRNA, and Wnt inhibitory activity, comparable to the observed effects of FH535 in OS (Bao et al, 2012; Quackenbush et al, 2016). Inhibitors of TNKS1/2 block Wnt signaling by reducing the PARylation of Axin2 by TNKS1/2.…”

Section: Resultsmentioning

confidence: 90%

FH535 Suppresses Osteosarcoma Growth In Vitro and Inhibits Wnt Signaling through Tankyrases

et al. 2017

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Osteosarcoma (OS) is an aggressive primary bone tumor which exhibits aberrantly activated Wnt signaling. The canonical Wnt signaling cascade has been shown to drive cancer progression and metastasis through the activation of β-catenin. Hence, small molecule inhibitors of Wnt targets are being explored as primary or adjuvant chemotherapy. In this study, we have investigated the ability of FH535, an antagonist of Wnt signaling, to inhibit the growth of OS cells. We found that FH535 was cytotoxic in all OS cell lines which were tested (143b, U2OS, SaOS-2, HOS, K7M2) but well tolerated by normal human osteoblast cells. Additionally, we have developed an in vitro model of doxorubicin-resistant OS and found that these cells were highly responsive to FH535 treatment. Our analysis provided evidence that FH535 strongly inhibited markers of canonical Wnt signaling. In addition, our findings demonstrate a reduction in PAR-modification of Axin2 indicating inhibition of the tankyrase 1/2 enzymes. Moreover, we observed inhibition of auto-modification of PARP1 in the presence of FH535, indicating inhibition of PARP1 enzymatic activity. These data provide evidence that FH535 acts through the tankyrase 1/2 enzymes to suppress Wnt signaling and could be explored as a potent chemotherapeutic agent for the control of OS.

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“…Over the past decade, various tankyrase inhibitors have been developed, some of which have been adapted to in vivo administration in preclinical models . Among such inhibitors, G007‐LK is one of the most studied tankyrase inhibitors in vivo, although it has only been given i.p .…”

Section: Discussionmentioning

confidence: 99%

“…IWR‐1 is another tankyrase inhibitor, initially identified as an Axin stabilizer . Although XAV939 and IWR‐1 are not suitable for in vivo experiments owing to their pharmacokinetic problems, several tankyrase‐specific inhibitors for in vivo administration have been developed, including G007‐LK, NVP‐TNKS656, K‐756, AZ1366, G‐631 and JW55 . G007‐LK inhibits proliferation of the colorectal cancer cells COLO‐320DM and SW403, both harboring truncated APC mutations, but not HCT‐15 and DLD‐1 cells, which also have truncated APC mutants .…”

Section: Introductionmentioning

confidence: 99%

RK‐287107, a potent and specific tankyrase inhibitor, blocks colorectal cancer cell growth in a preclinical model

et al. 2018

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Aberrant activation of Wnt/β‐catenin signaling causes tumorigenesis and promotes the proliferation of colorectal cancer cells. Porcupine inhibitors, which block secretion of Wnt ligands, may have only limited clinical impact for the treatment of colorectal cancer, because most colorectal cancer is caused by loss‐of‐function mutations of the tumor suppressor adenomatous polyposis coli (APC) downstream of Wnt ligands. Tankyrase poly(ADP‐ribosyl)ates (PARylates) Axin, a negative regulator of β‐catenin. This post‐translational modification causes ubiquitin‐dependent degradation of Axin, resulting in β‐catenin accumulation. Tankyrase inhibitors downregulate β‐catenin and suppress the growth of APC‐mutated colorectal cancer cells. Herein, we report a novel tankyrase‐specific inhibitor RK‐287107, which inhibits tankyrase‐1 and ‐2 four‐ and eight‐fold more potently, respectively, than G007‐LK, a tankyrase inhibitor that has been previously reported as effective in mouse xenograft models. RK‐287107 causes Axin2 accumulation and downregulates β‐catenin, T‐cell factor/lymphoid enhancer factor reporter activity and the target gene expression in colorectal cancer cells harboring the shortly truncated APC mutations. Consistently, RK‐287107 inhibits the growth of APC‐mutated (β‐catenin‐dependent) colorectal cancer COLO‐320DM and SW403 cells but not the APC‐wild (β‐catenin‐independent) colorectal cancer RKO cells. Intraperitoneal or oral administration of RK‐287107 suppresses COLO‐320DM tumor growth in NOD‐SCID mice. Rates of tumor growth inhibition showed good correlation with the behavior of pharmacodynamic biomarkers, such as Axin2 accumulation and MYC downregulation. These observations indicate that RK‐287107 exerts a proof‐of‐concept antitumor effect, and thus may have potential for tankyrase‐directed molecular cancer therapy.

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The novel tankyrase inhibitor (AZ1366) enhances irinotecan activity in tumors that exhibit elevated tankyrase and irinotecan resistance

Cited by 35 publications

References 36 publications

Wee1 inhibition can suppress tumor proliferation and sensitize p53 mutant colonic cancer cells to the anticancer effect of irinotecan

Wee1 inhibition can suppress tumor proliferation and sensitize p53 mutant colonic cancer cells to the anticancer effect of irinotecan

FH535 Suppresses Osteosarcoma Growth In Vitro and Inhibits Wnt Signaling through Tankyrases

RK‐287107, a potent and specific tankyrase inhibitor, blocks colorectal cancer cell growth in a preclinical model

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