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Sequence‐Dependent Sorafenib Therapy in Combination with Natural Phenolic Compounds for Hepatocellular Carcinoma and Possible Mechanism of Action
Author(s) -
Abaza Mohamed Salah,
Bahman AbdulMajed M,
Khoushiash Sarah,
AlAttiyah Rajaa
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.934.6
Subject(s) - sorafenib , curcumin , combination therapy , hepatocellular carcinoma , pharmacology , concomitant , apoptosis , chemistry , resveratrol , cancer research , medicine , biochemistry
Sorafenib (NexavarH, BAY43‐9006, Sora) is the first molecular targeted‐therapy that has shown significantly therapeutic benefits in advanced hepatocellular carcinoma (HCC). However, not all HCC patients respond to Sora well and new therapeutic strategies to optimize the efficacy of Sora are urgently required. The efficacy of plant‐based drugs has received growing attention due to their excellent chemotherapeutic and chemopreventive activities beside they are well tolerated, nontoxic, easily available, and inexpensive. It is well known that natural active compounds may act in synergy with drugs used in clinical applications. Therefore, this study aimed to investigate whether a combination therapy with natural phenolic compounds including curcumin (Cur), quercetin (Que), kaempferol (Kmf) and resveratrol (Rsv) may allow dose reduction of Sora without loss of effectiveness at the same time. HCC cell lines (Hep3b, HepG2) were treated with Sora alone or in combination with natural phenolic compounds in concomitant, sequential and inverted sequential regimens. Cell proliferation, cell cycle, apoptosis and expression of proteins‐related to cell cycle and apoptosis were investigated. Phenolic compounds markedly potentiated the therapeutic efficacy of Sora in a schedule‐, type and dose of phenolic compound‐, cell line‐dependent manner. Concomitant treatment with Cur (Sensitization ratio, SR= 28), Kmf (SR = 18), Que (SR= 8), was found to be associated with the highest SR in Hep3b. Rsv markedly potentiated Sora effect (SR = 17) on Hep3b when administered in reverse sequential manner. In contrast, Rsv and Que did not improve the efficacy of Sora on HepG2, meanwhile simultaneous treatment with Cur (SR =10) and Kmf (SR = 4.01) potentiated Sora cytotoxicity. Concomitant treatment with Sora and Cur or Kmf growth arrested HCC cells in S‐phase and G2/M‐phase and markedly induced apoptosis compared to single treatments with Sora, Cur and Kmf. Concomitant combined treatment with Sora and Cur reduced the protein levels of cyclins A, B2 and D1, phosphorylated retinoblastoma and BcLxL. On the other hand, Sora/Cur co‐treatment increased the protein levels of Bax, cleaved caspase‐3, and cleaved caspase‐9 in dose‐dependent manner. In conclusion, concomitant treatment with Sora and Cur or Kmf seems to be a potent and promising therapeutic approach that can control HCC by triggering cell cycle arrest and apoptosis. Additional studies need to be performed in order to exam the in vivo potential of the combined treatment of Sora and natural phenolic compounds. This study was supported by Kuwait University, Research Grant No. YS01/15.