A conjugate of an anti-midkine single-chain variable fragment to doxorubicin inhibits tumor growth

Zhao, Shuli; Zhao, Guangfeng; Xie, Hao; Huang, Yue; Hou, Yayi

doi:10.1590/s0100-879x2012007500009

Cited by 7 publications

(3 citation statements)

References 28 publications

(34 reference statements)

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“…We previously also found that MK was highly expressed in the gastric tumor tissues of Chinese patients and patients with malignant effusions [25, 26]. Both siRNA targeting MK gene and the conjugate (a single-chain variable fragment against human MK-Doxorubicin) inhibited gastric cancer cell growth and induced apoptosis [27, 28]. MK is therefore an attractive molecular target for cancer therapy.…”

Section: Introductionmentioning

confidence: 99%

Dihydroartemisinin and Curcumin Synergistically Induce Apoptosis in SKOV3 Cells Via Upregulation of MiR-124 Targeting Midkine

Zhao

Pan

et al. 2017

Cell Physiol Biochem

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Background/Aim: Women with advanced ovarian carcinoma are less likely to receive platinum-based chemotherapy and surgery due to a greater risk of cytotoxicity and poorer outcomes. We attempted to improve a promising therapy against ovarian cancer by using a combination of dihydroartemisinin (DHA) and curcumin (Cur). Methods: Human ovarian cancer SKOV3 cells were treated with DHA, Cur alone, or a combination of both. The viability of SKOV3 cells was measured by Cell Counting Kit-8 (CCK-8) and a colony formation assay. The cell cycle and apoptosis of SKOV3 cells were monitored by flow cytometry. The mRNA and protein expression levels of target genes were respectively examined by qRT-PCR and western blot. The biological effects of miR-124 on midkine (MK) were verified by a luciferase activity analysis. Results: Combined treatment of DHA and Cur synergistically decreased cell viability, arrested cell cycle, and promoted apoptosis in SKOV3 cells. Moreover, it significantly attenuated the expression of oncogene MK and synergistically upregulated the expression of miR-124. Furthermore, miR-124 was verified to bind directly to the 3ʹ-untranslated region of MK mRNA, resulting in mRNA degradation and reduced MK protein levels. The combination of DHA with Cur significantly inhibited tumor growth in xenograft nude mice without obvious toxicity. Conclusion: Co-treatment with DHA and Cur exhibited a synergistic anti-tumor effect on SKOV3 cells both in vitro and in vivo.

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Section: Introductionmentioning

confidence: 99%

Dihydroartemisinin and Curcumin Synergistically Induce Apoptosis in SKOV3 Cells Via Upregulation of MiR-124 Targeting Midkine

Zhao

Pan

et al. 2017

Cell Physiol Biochem

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“…Ongoing researches showed that optimal linkers and payloads are required to match scFv properties like aggregation, binding, and stability [ 30 ]. An early SDC comprised scFv-DOX at 1:20 ratio via polyaldodextraven (PAD) linkage, exhibiting potent cytotoxicity toward MK+ cells and inhibition of tumor growth in vivo [ 31 ]. Another method to prepare SDCs is fusion protein through gene editing.…”

Section: Based On Antibody Fragmentsmentioning

confidence: 99%

Reforming solid tumor treatment: the emerging potential of smaller format antibody-drug conjugate

Ma,

Wang,

Ying

et al. 2024

Antibody Therapeutics

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In recent years, substantial therapeutic efficacy of antibody-drug conjugates (ADCs) has been validated through approvals of 16 ADCs for the treatment of malignant tumors. However, realization of the maximum clinical use of ADCs requires surmounting extant challenges, mainly the limitations in tumor penetration capabilities when targeting solid tumors. To resolve the hurdle of suboptimal tumor penetration, miniaturized antibody fragments with engineered formats have been harnessed for ADC assembly. By virtue of their reduced molecular sizes, antibody fragment-drug conjugates (FDCs) hold considerable promise for efficacious delivery of cytotoxic agents, thus conferring superior therapeutic outcomes. This review will focus on current advancements in novel ADC development utilizing smaller antibody formats from approximately 6 to 80 kDa, with particular emphasis on single-domain antibodies, which have been widely applied in novel ADC design. Additionally, strategies to optimize clinical translation are discussed, including half-life extension, acceleration of internalization, and reduction of immunogenic potential.

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“…28 It is a promising prognostic/diagnostic marker of cancer, 29 and its blockade is found to contribute to tumor cell proliferation. 30,31 Thus we explored the effect of D261 on MK expression, as assessing its anti-proliferation activity in vivo. After three weeks of therapy with or without D261, tumors were removed from nude mice and the mRNA level of MK was assessed by qRT-PCR assay.…”

Section: D261 Suppresses Growth Of Nci-h460 Xenografts In Vivomentioning

confidence: 99%

A novel small-molecule compound diaporine A inhibits non-small cell lung cancer growth by regulating miR-99a/mTOR signaling

Song

Dou

Wang

et al. 2014

Cancer Biology & Therapy

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Abbreviations: NSCLC, non-small cell lung cancer; CDK, cyclin-dependent kinase; mTOR, mammalian target of rapamycin; p70S6K, ribosomal protein S6 kinase (70KD); CFSE, carboxyfluorescein diacetate succinimidyl ester; MK, midkine; miRNAs, microRNAsMicroRNas (miRNas) dysregulation is critically involved in lung cancer. Regulating miRNas by natural agents may be a new strategy for cancer treatment. We previously found that a novel small-molecule compound diaporine a (D261), a natural product of endophytic fungus 3lp-10, had potential anti-cancer activites. In the present study, the inhibitory effect of D261 on non-small cell lung cancer (NscLc) growth and its possible mechanisms involving miRNa regulation were investigated. By cell viability assay, cell proliferation analysis, and clonal growth assay, we proved that D261 effectively inhibited the proliferation of NscLc cells (NcI-h460 and a549) in vitro. administration of D261 (5 mg/kg) to NcI-h460 xenografts bearing mice also inhibited tumor growth and decreased the expression of cell proliferation regulator, midkine. Moreover, D261 induced cell cycle arrest with a reduced expression of various G 1 /s transition-related molecules including cyclin D1, cyclin e1, cDK4, and cDK2, but without influencing apoptosis in NscLc cells. Intriguingly, D261 modified expressions of some miRNas and especially upregulated miR-99a, whose direct target was mammalian target of rapamycin (mTOR). Furthermore, overexpression of miR-99a antagonized the anti-tumor actions of D261 including the suppression of mTOR pathway activation, cell cycle-related proteins and cell growth. In addition, blocking of miR-99a expression by transfection of miR-99a inhibitors before D261 treatment counteracted the anti-tumor effects of D261. These data suggest that miR-99a/mTOR pathway was involved in D261-induced tumor suppression in NscLc cells. D261 might be a potent anti-cancer agent by upregulating miR-99a expression.

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A conjugate of an anti-midkine single-chain variable fragment to doxorubicin inhibits tumor growth

Cited by 7 publications

References 28 publications

Dihydroartemisinin and Curcumin Synergistically Induce Apoptosis in SKOV3 Cells Via Upregulation of MiR-124 Targeting Midkine

Dihydroartemisinin and Curcumin Synergistically Induce Apoptosis in SKOV3 Cells Via Upregulation of MiR-124 Targeting Midkine

Reforming solid tumor treatment: the emerging potential of smaller format antibody-drug conjugate

A novel small-molecule compound diaporine A inhibits non-small cell lung cancer growth by regulating miR-99a/mTOR signaling

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