The combination of olaratumab with gemcitabine and docetaxel arrests a chemotherapy-resistant undifferentiated soft-tissue sarcoma in a patient-derived orthotopic xenograft mouse model

Higuchi, Takashi; Miyake, Kentaro; Sugisawa, Norihiko; Oshiro, Hiromichi; Zhang, Zhiying; Razmjooei, Sahar; Yamamoto, Norio; Hayashi, Katsuhiro; Kimura, Hiroaki; Miwa, Shinji; Igarashi, Kentaro; Bouvet, Michael; Singh, Shree Ram; Tsuchiya, Hiroyuki; Hoffman, Robert M.

doi:10.1007/s00280-019-03824-3

Cited by 7 publications

(4 citation statements)

References 38 publications

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“…27 Combination therapy based on gemcitabine and other active antitumor agents could provide a modest improvement in survival. 28 For example, compared with gemcitabine alone, gemcitabine and harmine combination therapy provides enhanced therapeutic benefit in pancreatic cancer. 29 Consequently, it is of great interest to identify new therapeutic agents to increase the chemosensitivity of gemcitabine and develop novel combination-therapy approaches.…”

Section: Dovepressmentioning

confidence: 99%

<p>Saikosaponin D Inhibits Proliferation and Promotes Apoptosis Through Activation of MKK4–JNK Signaling Pathway in Pancreatic Cancer Cells</p>

Lai

Chen

et al. 2020

OTT

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Introduction: Pancreatic cancer remains one of the most lethal malignancies and has few treatment options. Saikosaponin D (SSD), a major bioactive triterpene saponin isolated from Bupleurum chinense, has been reported to exert cytotoxicity properties toward many cancer cells. However, the effects of SSD on pancreatic cancer have been little scrutinized. Methods: Here, we investigated the effect of SSD on the proliferation and apoptosis of human pancreatic cancer BxPC3 and PANC1 cells and the mouse pancreatic cancer cell line Pan02. Cell viability was determined by MTT assays and cell apoptosis analyzed by DAPI staining and flow cytometry. Expression levels of apoptosis-regulating markers and activity of the MKK4-JNK signaling pathway were determined by Western blotting. The inhibitor SP600125 was applied to confirm the role of the JNK pathway in SSD efficiency. Results: SSD significantly inhibited the proliferation of BxPC3, PANC1, and Pan02 cells in a concentration-and time-dependent manner. Flow-cytometry analysis indicated obvious apoptosis induction after SSD exposure. Furthermore, SSD significantly triggered cleavage of caspase 3 and caspase 9 proteins and increased the expression of FoxO3a. In addition, activity of the MKK4-JNK pathway was dramatically increased after treatment with SSD in BxPC3 cells. SSD obviously stimulated phosphorylation of JNK, cJun, and SEK1/MKK4 proteins within 30 minutes. The addition of SP600125 blocked the activation of SSD on the MKK4-JNK regulatory pathway and reversed the effects of SSD on proliferation inhibition and apoptosis induction in BxPC3 cells. Conclusion: These results revealed that SSD was capable of suppressing tumor growth and promoting apoptosis of pancreatic cancer cells via targeting the MKK4-JNK signaling pathway, indicating the possibility of further developing SSD as a potential therapeutic candidate for pancreatic cancer.

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Section: Dovepressmentioning

confidence: 99%

<p>Saikosaponin D Inhibits Proliferation and Promotes Apoptosis Through Activation of MKK4–JNK Signaling Pathway in Pancreatic Cancer Cells</p>

Lai

Chen

et al. 2020

OTT

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“…In spite of novel approaches being currently investigated, as the use of nanotechnology to increase its therapeutic potential [6], resistance to gemcitabine is still a major challenge [7]. In addition, gemcitabine has been combined with other chemotherapeutic agents, including traditional drugs as cisplatin [8], Tyrosine Kinase inhibitors [9] or specific antibodies as Olaratumab [10]. Furthermore, combination of gemcitabine with radiotherapy has shown promising results in several pathologies [11,12].…”

Section: Introductionmentioning

confidence: 99%

p38β (MAPK11) mediates gemcitabine-associated radiosensitivity in sarcoma experimental models

Pascual-Serra

Fernández-Aroca

Sabater

et al. 2021

Radiotherapy and Oncology

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“…OLA plus DOX showed an acceptable safety profile in Japanese patients with STS [29]. The combination of OLA with gemcitabine and docetaxel arrested the tumor growth in drug-resistant STS [30]. In addition, OLA together with DOX and ifosfamide arrested the growth of DOX- and OLA-resistance undifferentiated STS [31].…”

Section: Discussionmentioning

confidence: 95%

The Combination of Olaratumab with Doxorubicin and Cisplatinum Regresses a Chemotherapy-Resistant Osteosarcoma in a Patient-Derived Orthotopic Xenograft Mouse Model

Higuchi

Sugisawa

Miyake

et al. 2019

Translational Oncology

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Chemotherapy-resistant osteosarcoma is a recalcitrant disease. It is a frequent cause of death to the patients who are usually adolescent or young adults. The goal of the present study was to determine the efficacy of the combination of olaratumab (OLA), doxorubicin (DOX), and cisplatinum (CDDP) on osteosarcoma, which is resistant to first-line therapy, in a patient-derived orthotopic xenograft (PDOX) model. The osteosarcoma PDOX model was randomized into six treatment groups of six mice: control; CDDP alone; DOX and CDDP; OLA + DOX; OLA + CDDP; and OLA + DOX and CDDP. Tumor size and body weight were measured during 14 days of treatment. Tumor growth was regressed only by the treatment with a combination of OLA + DOX and CDDP. Tumors treated with this three-drug combination had the most tumor necrosis and the lowest Ki-67 index. The present study demonstrates the power of the PDOX model to identify novel effective treatment strategy for chemotherapy-resistant osteosarcoma.

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The combination of olaratumab with gemcitabine and docetaxel arrests a chemotherapy-resistant undifferentiated soft-tissue sarcoma in a patient-derived orthotopic xenograft mouse model

Cited by 7 publications

References 38 publications

<p>Saikosaponin D Inhibits Proliferation and Promotes Apoptosis Through Activation of MKK4–JNK Signaling Pathway in Pancreatic Cancer Cells</p>

<p>Saikosaponin D Inhibits Proliferation and Promotes Apoptosis Through Activation of MKK4–JNK Signaling Pathway in Pancreatic Cancer Cells</p>

p38β (MAPK11) mediates gemcitabine-associated radiosensitivity in sarcoma experimental models

The Combination of Olaratumab with Doxorubicin and Cisplatinum Regresses a Chemotherapy-Resistant Osteosarcoma in a Patient-Derived Orthotopic Xenograft Mouse Model

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