Drug Discovery Using Evolutionary Similarities in Chemical Binding to Inhibit Patient-Derived Hepatocellular Carcinoma

Lim, Jin Hong; Park, Keunwan; Choi, Kyung Hwa; Kim, Chan Wung; Lee, Jaeha; Weicker, Raymond; Pan, Cheol‐Ho; Kim, Seok Mo; Park, Ki Cheong

doi:10.3390/ijms23147971

Cited by 5 publications

(9 citation statements)

References 74 publications

(83 reference statements)

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“…We focused on the signaling pathway of calcium that was enormously induced in sorafenib-resistant PTC cells. Furthermore, there was a slight difference between SERCA isoforms; however, of particular importance was the basal expression level of SERCA , which is an acute regulator of calcium homeostasis and anti-apoptosis [ 24 , 29 , 30 , 31 ]. These were increased in YUMC-R-P1, -P2, and -P3 sorafenib-resistant PTC cells compared with that in sorafenib-sensitive PTC cells, YUMC-S-P1 ( Figure 1 D).…”

Section: Resultsmentioning

confidence: 99%

“…In this study, despite the broadly known anti-cancer efficacy of sorafenib, it did not notably influence human sorafenib-resistant PTC cells. In our published papers, we proposed that metabolic stress-resistant cancer cells evaded apoptosis by cytoplasmic-free Ca 2+ overburden via SERCA increase under severe ER stress conditions [ 31 , 66 , 67 ]. The present study showed that regardless of the extreme increase in SERCA expression in sorafenib-resistant PTC cells, the functional restriction of SERCA by the novel SERCA inhibitors, candidates 24 or 31, could lead to severe ER stress-mediated apoptosis.…”

Section: Discussionmentioning

confidence: 99%

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Anti-Cancer SERCA Inhibitors Targeting Sorafenib-Resistant Human Papillary Thyroid Carcinoma

Chang

Kim

Lee

et al. 2023

IJMS

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Thyroid cancer is generally curable and, in many cases, can be completely treated, although it can sometimes recur after cancer therapy. Papillary thyroid cancer (PTC) is known as one of the most general subtypes of thyroid cancer, which take up nearly 80% of whole thyroid cancer. However, PTC may develop anti-cancer drug resistance via metastasis or recurrence, making it practically incurable. In this study, we propose a clinical approach that identifies novel candidates based on target identification and validation of numerous survival-involved genes in human sorafenib-sensitive and -resistant PTC. Consequently, we recognized a sarco/endoplasmic reticulum calcium ATPase (SERCA) in human sorafenib-resistant PTC cells. Based on the present results, we detected novel SERCA inhibitor candidates 24 and 31 via virtual screening. These SERCA inhibitors showed remarkable tumor shrinkage in the sorafenib-resistant human PTC xenograft tumor model. These consequences would be clinically worthwhile for the development of a new combinatorial strategy that effectively targets incredibly refractory cancer cells, such as cancer stem cells and anti-cancer drug-resistant cells.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Anti-Cancer SERCA Inhibitors Targeting Sorafenib-Resistant Human Papillary Thyroid Carcinoma

Chang

Kim

Lee

et al. 2023

IJMS

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“…Furthermore, the calcium signaling pathways were also highly enhanced in paclitaxel- or sorafenib-resistant PTC cells ( Figure 2 D–F). Furthermore, basal levels of the protein expression of SERCA, which is a critical player in apoptosis and calcium homeostasis [ 23 , 28 , 29 , 30 ], were higher in YUMC-R-P1, -P2, and -P3 than in YUMC-S-P1 cells ( Figure 2 G). Moreover, after exposure to paclitaxel or sorafenib, the levels of expression of SERCA significantly increased in YUMC-R-P1, -P2, and -P3 compared to YUMC-S-P1 cells ( Figure 2 G).…”

Section: Resultsmentioning

confidence: 99%

“…Cell viability was measured using the MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) assay; cells were seeded in 96-well plates at 7 × 10 3 cells per well and incubated overnight to achieve 80% confluency. The detailed protocol can be found in our previous article [ 30 ]. Data were expressed as a percentage of the signal observed in vehicle-treated cells and are shown as the means ± SEM of triplicate experiments.…”

Section: Methodsmentioning

confidence: 99%

Potential Therapeutic Agents against Paclitaxel—And Sorafenib-Resistant Papillary Thyroid Carcinoma

Kim

Park²,

Lim

et al. 2022

IJMS

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Thyroid carcinoma, a disease in which malignant cells form in the thyroid tissue, is the most common endocrine carcinoma, with papillary thyroid carcinoma (PTC) accounting for nearly 80% of total thyroid carcinoma cases. However, the management of metastatic or recurrent therapy-refractory PTC is challenging and requires complex carcinoma therapy. In this study, we proposed a new clinical approach for the treatment of therapy-refractory PTC. We identified sarco/endoplasmic reticulum calcium ATPase (SERCA) as an essential factor for the survival of PTC cells refractory to the treatment with paclitaxel or sorafenib. We validated its use as a potential target for developing drugs against resistant PTC, by using patient-derived paclitaxel- or sorafenib-resistant PTC cells. We further discovered novel SERCA inhibitors, candidates 7 and 13, using the evolutionary chemical binding similarity method. These novel SERCA inhibitors determined a substantial reduction of tumors in a patient-derived xenograft tumor model developed using paclitaxel- or sorafenib-resistant PTC cells. These results could provide a basis for clinically meaningful progress in the treatment of refractory PTC by identifying a novel therapeutic strategy: using a combination therapy between sorafenib or paclitaxel and specific SERCA inhibitors for effectively and selectively targeting extremely malignant cells such as antineoplastic-resistant and carcinoma stem-like cells.

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“…This is accomplished by increasing SERCA expression, thereby permitting survival under metabolically challenging conditions. Previously, we demonstrated potential results for applying novel combinatorial strategies and discovering anti-cancer candidates that SERCA-targeted a speci c vulnerability of patient-derived anti-cancer drug-resistant cancer cells [20,21]. However, a cardiac dysfunction was inevitable in xenograft model because of nonspeci c inhibition of SERCA isoforms by several candidates [20,21].…”

Section: Introductionmentioning

confidence: 99%

Survival of drug-resistant metastatic papillary thyroid cancer under drug treated conditions via upregulation of sarco/endoplasmic reticulum calcium ATPase 1

Kim,

Park,

Yun

et al. 2024

Preprint

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Background: Papillary thyroid cancer (PTC) is a general thyroid cancer subtype, however, PTC may develop metastasize or become recurrent via anti-cancer drug resistance, rendering it practically incurable. Therefore, effective and reliable clinical approaches are urgently required. Methods: In this study, we demonstrated the coordinated upregulation of SERCA1 in metastatic PTC under anti-cancer drug treated conditions. SERCA1, in turn, is transcriptionally upregulated by CaMK2α via nuclear translocated NFκB. we propose a clinical approach that screens novel drug candidates based on target identification and numerous survival-involved gene validation in a patient-derived anti-cancer drug-resistant mediated lymph node metastatic PTC model. Results of lymph node metastatic PTC was compared to anti-cancer drug sensitive and main mass PTC on in vitro and in vivo model. Results: Consequently, we identified sarco/endoplasmic reticulum (ER) calcium ATPase 1 (SERCA1) in patient-derived metastatic PTC cells. SERCA1 was considerably increase under anti-cancer drug treated conditions such as sorafenib or lenvatinib by CaMK2α mediated nuclear translocated NFκB. SERCA is a critical component in cytosolic free calcium regulation. However, a cardiac dysfunction was inevitable in vivo because of non-specific inhibition of SERCA isoforms by conventional SERCA inhibitors. This study aimed to design a therapeutic approach with decrease of cardiac dysfunction via SERCA1-isoform specific inhibition by novel small molecules, CKP1 and CKP2 under severe ER stress condition in patient-derived metastatic papillary thyroid cancer. These novel SERCA1-specific inhibitors were remarkably increased tumor shrinkage in the patient-derived metastatic PTC xenograft tumor model without cardiac dysfunctionwhen combination treatment with anti-cancer drug, such as sorafenib and lenvatinib. Conclusively, these findings are clinically significant for novel combinatorial strategy development for effective refractory cancer cell treatments, especially in the case of anti-cancer drug-resistant mediated recurrent and metastatic cancer. Conclusions Here, we showed that increase of SERCA1 by CaMK2α mediated nuclear translocated NFκB was fundamentally responsible for cellular resistant for cytotoxic stress under sorafenib or levatinib treatment. These outcomes suggest progress for the novel combinatorial scheme that uses targeted therapy to treat malignant cancer cells, such as anti-cancer drug-resistant cancer cells.

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Drug Discovery Using Evolutionary Similarities in Chemical Binding to Inhibit Patient-Derived Hepatocellular Carcinoma

Cited by 5 publications

References 74 publications

Anti-Cancer SERCA Inhibitors Targeting Sorafenib-Resistant Human Papillary Thyroid Carcinoma

Anti-Cancer SERCA Inhibitors Targeting Sorafenib-Resistant Human Papillary Thyroid Carcinoma

Potential Therapeutic Agents against Paclitaxel—And Sorafenib-Resistant Papillary Thyroid Carcinoma

Survival of drug-resistant metastatic papillary thyroid cancer under drug treated conditions via upregulation of sarco/endoplasmic reticulum calcium ATPase 1

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