A novel small molecule LLL12B inhibits STAT3 signaling and sensitizes ovarian cancer cell to paclitaxel and cisplatin

Zhang, Ruijie; Yang, Xiaozhi; Roque, Dana M.; Li, Chenglong; Lin, Jiayuh

doi:10.1371/journal.pone.0240145

Cited by 10 publications

(14 citation statements)

References 45 publications

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“…We applied a 3-D in vitro ADM model by which primary mouse pancreatic acini dedifferentiate when cultured on the extracellular matrix Matrigel [ 1 ]. We show that a pStat3 inhibitor LLL12B [ 10 , 11 ] and a HDAC inhibitor TSA impede ADM in p48 Cre/+ and p48 Cre/+ ;LSL-Kras G12D/+ (KC) mouse organoids. Furthermore, addition of the compounds to mouse or human tissue cultures after ADM had occurred, resulted in cellular and gene expression changes that suggest a reversal of the dedifferentiated phenotype to one that is more acinar-like.…”

Section: Introductionmentioning

confidence: 99%

Pharmacological inhibition and reversal of pancreatic acinar ductal metaplasia

et al. 2022

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Pancreatic acinar cells display a remarkable degree of plasticity and can dedifferentiate into ductal-like progenitor cells by a process known as acinar ductal metaplasia (ADM). ADM is believed to be one of the earliest precursor lesions toward the development of pancreatic ductal adenocarcinoma and maintaining the pancreatic acinar cell phenotype suppresses tumor formation. The effects of a novel pStat3 inhibitor (LLL12B) and the histone deacetylase (HDAC) inhibitor trichostatin A (TSA) were investigated using 3-D cultures from p48Cre/+ and p48Cre/+LSL-KrasG12D/+ (KC) mice. LLL12B and TSA inhibited ADM in both KC and p48Cre/+ mouse pancreatic organoids. Furthermore, treatment with LLL12B or TSA on dedifferentiated acini from p48Cre/+ and KC mice that had undergone ADM produced morphologic and gene expression changes that suggest a reversal of ADM. Validation experiments using qRT-PCR (p48Cre/+ and KC) and RNA sequencing (KC) of the LLL12B and TSA treated cultures showed that the ADM reversal was more robust for the TSA treatments. Pathway analysis showed that TSA inhibited Spink1 and PI3K/AKT signaling during ADM reversal. The ability of TSA to reverse ADM was also observed in primary human acinar cultures. We report that pStat3 and HDAC inhibition can attenuate ADM in vitro and reverse ADM in the context of wild-type Kras. Our findings suggest that pharmacological inhibition or reversal of pancreatic ADM represents a potential therapeutic strategy for blocking aberrant ductal reprogramming of acinar cells.

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Section: Introductionmentioning

confidence: 99%

Pharmacological inhibition and reversal of pancreatic acinar ductal metaplasia

et al. 2022

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“…It has been shown that LLL12B induced apoptosis, suppressed tumor growth, and exhibited synergistic activity in combination with cisplatin or irradiation in medulloblastoma cells [ 25 , 31 ]. In addition, LLL12B sensitized ovarian cancer cells to paclitaxel and cisplatin [ 45 ]. In this study, we evaluated the inhibitory effects of LLL12B on TNBC cells in vitro and in vivo.…”

Section: Discussionmentioning

confidence: 99%

LLL12B, a Novel Small-Molecule STAT3 Inhibitor, Induces Apoptosis and Suppresses Cell Migration and Tumor Growth in Triple-Negative Breast Cancer Cells

et al. 2022

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Persistent STAT3 signaling plays a pivotal role in human tumor malignancy, including triple-negative breast cancer (TNBC). There are few treatment options currently available for TNBC; thus, given its importance to cancer, STAT3 is a potential cancer therapeutic target and is the focus of drug discovery efforts. In this study, we tested a novel orally bioavailable small-molecule STAT3 inhibitor, LLL12B, in human MDA-MB-231, SUM159, and murine 4T1 TNBC cell lines. TNBC cells frequently expressed persistent STAT3 phosphorylation and their cell viability was sensitive to STAT3 knockdown by siRNA. LLL12B selectively inhibited the IL-6-mediated induction of STAT3 phosphorylation, but had little effect on the IFN-γ-mediated induction of STAT1 phosphorylation nor the EGF-mediated induction of ERK phosphorylation. In addition, targeting STAT3 with LLL12B induced apoptosis, reduced colony formation ability, and inhibited cell migration in TNBC cells. Furthermore, LLL12B suppressed the tumor growth of the MDA-MB-231 TNBC cells in a mammary fat pad mouse tumor model in vivo. Together, our findings support the concept that targeting persistent STAT3 signaling using the novel small-molecule LLL12B is a potential approach for TNBC therapy.

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“…The HIPEC model that was adapted could forecast the bioactive utilisation of cisplatin by regression analysis [ 160 ]. Cisplatin combined with the taxanes is another chemotherapeutic regimen in attenuating OC, but its efficacy is reduced by chemoresistance of the OC cells [ 101 ]. LLL12B is a small molecule inhibitor of chemoresistance that showed improved sensitivity when administered in combination with both cisplatin and paclitaxel together compared to either cisplatin or paclitaxel alone [ 101 ].…”

Section: Recent Advances In Cisplatin-associated Ovarian Cancermentioning

confidence: 99%

“…Cisplatin combined with the taxanes is another chemotherapeutic regimen in attenuating OC, but its efficacy is reduced by chemoresistance of the OC cells [ 101 ]. LLL12B is a small molecule inhibitor of chemoresistance that showed improved sensitivity when administered in combination with both cisplatin and paclitaxel together compared to either cisplatin or paclitaxel alone [ 101 ]. It suppressed cell viability and proliferation by downregulating the signal transducer and activator of transcription-3 (STAT3) pathway [ 101 ].…”

Section: Recent Advances In Cisplatin-associated Ovarian Cancermentioning

confidence: 99%