Phosphonooxymethyl Prodrug of Triptolide: Synthesis, Physicochemical Characterization, and Efficacy in Human Colon Adenocarcinoma and Ovarian Cancer Xenografts

Patil, Sachin; Lis, L. G.; Schumacher, Robert J.; Norris, Beverly; Morgan, Monique; Cuellar, Rebecca A. D.; Blazar, Bruce R.; Suryanarayanan, Raj; Gurvich, Vadim J.; Georg, Gunda I.

doi:10.1021/acs.jmedchem.5b01329

Cited by 67 publications

(45 citation statements)

References 56 publications

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“…Natural products are important in cancer chemotherapy due to their beneficial pharmacological activities and low toxicity. Tumor therapy with traditional Chinese herbs, including curcumin ( 7 – 9 ), triptolide ( 10 ) and Danshen ( 11 ) is becoming increasingly attractive ( 12 ). Shikonin (SK), an effective constituent purified from the Chinese medicinal herb, Lithospermum erythrorhixon , has been shown to exert antitumor effects by inhibiting pyruvate kinase-M2 (PKM2).…”

Section: Introductionmentioning

confidence: 99%

Shikonin promotes adriamycin-induced apoptosis by upregulating caspase-3 and caspase-8 in osteosarcoma

Yang

et al. 2017

Molecular Medicine Reports

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Osteosarcoma is the most common primary malignant bone tumor. Cancer cells employ a host of mechanisms to develop resistance to adriamycin (ADM) or other chemotherapeutic drugs. Shikonin (SK), an active constituent extracted from a Chinese medicinal herb, has been shown to cooperate with ADM in the treatment of osteosarcoma and certain other types of cancer by contributing to the response rate of chemotherapy and the side effects. The aim of the present study was to investigate the role and underlying mechanism of SK in chemotherapy for osteosarcoma. In the present study, a CCK-8 assay was performed to assess cell survival rate in vitro. Western blot analysis was performed to determine the expression levels of B-cell lymphoma 2-associated X protein (Bax), caspase-3, caspase-8, and poly (ADP-ribose) polymerase (PARP). Flow cytometry was used to analyze cell cycle and cell death. The survival rate of cells decreased significantly in a dose- and time-dependent manner when treated with a combination of SK and ADM. Western blot analysis revealed increased expression levels of Bax, caspase-3, caspase-8 and PARP in U2OS and MG63 cells 48 h following treatment with SK and ADM. Flow cytometric analysis showed that the combined treatment of SK and ADM significantly induced apoptosis in the osteosarcoma cells. Taken together SK cooperated with ADM to promote apoptosis, possibly by inducing caspase-3- and caspase-8-dependent apoptosis. SK may be a potential enhancer in the treatment of drug-resistant primary osteosarcoma.

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Section: Introductionmentioning

confidence: 99%

Shikonin promotes adriamycin-induced apoptosis by upregulating caspase-3 and caspase-8 in osteosarcoma

Yang

et al. 2017

Molecular Medicine Reports

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“…The high EE 1 and EE 2 of PAT could avoid the poor aqueous solubility and allow rapid parenteral infusion without the risk of drug precipitation. 44 In vitro release profile…”

Section: Characterization Of Patmentioning

confidence: 99%

Fabrication of a triptolide-loaded and poly-γ-glutamic acid-based amphiphilic nanoparticle for the treatment of rheumatoid arthritis

Zhang¹,

Chang²,

Zhao³

et al. 2018

IJN

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Triptolide (TP) exhibits immunosuppressive, cartilage-protective and anti-inflammatory effects in rheumatoid arthritis. However, the toxicity of TP limits its widespread use. To decrease the toxic effects, we developed a novel nano-drug carrier system containing TP using poly-γ-glutamic acid-grafted di-tert-butyl L-aspartate hydrochloride (PAT). PAT had an average diameter of 79±18 nm, a narrow polydispersity index (0.18), a strong zeta potential (−32 mV) and a high drug encapsulation efficiency (EE1=48.6%) and loading capacity (EE2=19.2%), and exhibited controlled release (t1/2=29 h). The MTT assay and flow cytometry results indicated that PAT could decrease toxicity and apoptosis induced by free TP on RAW264.7 cells. PAT decreased lipopolysaccharides/interferon γ-induced cytokines expression of macrophage (P<0.05). In vivo, PAT accumulated at inflammatory joints, improved the survival rate and had fewer side effects on tumor necrosis factor α transgenic mice, compared to TP. The blood biochemical indexes revealed that PAT did not cause much damage to the kidney (urea nitrogen and creatinine) and liver (alanine aminotransferase and aspartate aminotransferase). In addition, PAT reduced inflammatory synovial tissue area (P<0.05), cartilage loss (P<0.05), tartrate-resistant acid phosphatase-positive osteoclast area (P<0.05) and bone erosion (P<0.05) in both knee and ankle joints, and showed similar beneficial effect as free TP. In summary, our newly formed nanoparticle, PAT, can reduce the toxicity and guarantee the efficacy of TP, which represents an effective drug candidate for RA with low adverse side effect.

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“…Triptolide has poor aqueous solubility. To overcome this problem, the disodium phosphonooxymethyl prodrug of triptolide (49) is designed to target various cancers like pancreatic, breast and prostate cancers (Patil et al, 2015).…”

Section: Triptolide Prodrugmentioning

confidence: 99%

Natural product as a source of prodrug

Padmavathy¹,

Saravanan

2017

Bangladesh J Pharmacol

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<p class="Abstract">The natural products are the chemical constituents that are generated from the living organism. The natural products are isolated from the plants, animals, and microorganisms which are used in drug design and drug discovery. Natural product is then modified by chemical synthesis as either total or semi-synthetic way. The natural products show various pharmacological activity which can be used for the treatment of a variety of diseases. Natural products could be regarded as a source of quantifiable and chemically pure known products and also natural products can be utilized as complex mixtures subjected to chemical variability. The present review article adds up the prodrugs from natural products as well as prodrugs developed from the natural products.</p>

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Phosphonooxymethyl Prodrug of Triptolide: Synthesis, Physicochemical Characterization, and Efficacy in Human Colon Adenocarcinoma and Ovarian Cancer Xenografts

Cited by 67 publications

References 56 publications

Shikonin promotes adriamycin-induced apoptosis by upregulating caspase-3 and caspase-8 in osteosarcoma

Shikonin promotes adriamycin-induced apoptosis by upregulating caspase-3 and caspase-8 in osteosarcoma

Fabrication of a triptolide-loaded and poly-γ-glutamic acid-based amphiphilic nanoparticle for the treatment of rheumatoid arthritis

Natural product as a source of prodrug

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Phosphonooxymethyl Prodrug of Triptolide: Synthesis, Physicochemical Characterization, and Efficacy in Human Colon Adenocarcinoma and Ovarian Cancer Xenografts

Cited by 67 publications

References 56 publications

Shikonin promotes adriamycin-induced apoptosis by upregulating caspase-3 and caspase-8 in osteosarcoma

Shikonin promotes adriamycin-induced apoptosis by upregulating caspase-3 and caspase-8 in osteosarcoma

Fabrication of a triptolide-loaded and poly-&gamma;-glutamic acid-based amphiphilic nanoparticle for the treatment of rheumatoid arthritis

Natural product as a source of prodrug

Contact Info

Product

Resources

About

Fabrication of a triptolide-loaded and poly-γ-glutamic acid-based amphiphilic nanoparticle for the treatment of rheumatoid arthritis