Enhancement of oxaliplatin sensitivity in human colorectal cancer by hypericin mediated photodynamic therapy via ROS-related mechanism

Lin, Shengchao; Lei, Kecheng; Du, Wenpei; Yang, Liyan; Shi, Haiyang; Gao, Yuwei; Yin, Peihao; Liang, Xin; Liu, Jianwen

doi:10.1016/j.biocel.2015.12.003

Cited by 41 publications

(28 citation statements)

References 48 publications

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“…More significantly, Lin et al observed that ROS-related mechanisms increased oxaliplatin sensitivity in human colorectal cancers (10). Thus, in the present study, we present the first evidence that ROS distribution mediated by Cx43 contributes to the resistance of oxaliplatin in the treatment of human CRC.…”

Section: Introductionsupporting

confidence: 70%

Deficiency of gap junction composed of connexin43 contributes to oxaliplatin resistance in colon cancer cells

Zhang

2017

Oncology Letters

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Abstract. Although comprehensive strategies in the treatment of colorectal cancer have been developed for a number of years, the five-year survival rate of metastatic colon cancer remains less than 10%. Oxaliplatin, a commonly used chemotherapeutic agent for metastatic colon cancer, improves the response rate of patients and prolongs patients' progression-free survival. However, the generation of resistance limits the clinical application of oxaliplatin, and the mechanisms of this remain unclear. The present study mainly investigated the effect of the gap junction (GJ) composed of connexin43 (Cx43) on oxaliplatin cytotoxicity in colon cancer cells. Three different methods with distinct mechanisms were used to change the function of Cx43 GJs, including cell culture at different densities, pretreatment with a specific inhibitor or enhancer, and special gene knockdown, to observe the cytotoxicity of oxaliplatin and the level of reactive oxygen species (ROS) mediated by Cx43 GJs. The results revealed that the cytotoxicity of oxaliplatin and the level of ROS were decreased with the downregulation of Cx43 GJ function, but exacerbated with the upregulation of Cx43 GJ function. Moreover, ROS scavenging with N-acetyl-L-cysteine and apocynin decreased the cytotoxicity of oxaliplatin. We concluded that the loss of GJ composed of Cx43 contributed to the resistance of oxaliplatin in colon cancer cells, and the mechanism was associated with intracellular ROS alternation. IntroductionColorectal cancer (CRC) is considered to be one of the most frequent causes of cancer-related morbidity and mortality worldwide (1,2). Although comprehensive strategies in the treatment of CRC have been developed for a number of years, the five-year survival rate of metastatic colon cancer is only 10% (3). In the clinical treatment of metastatic colon cancer, oxaliplatin is commonly used as an essential chemotherapeutic agent, and not only improves the response rate of patients, but also prolongs patients' progression-free survival. Nevertheless, more than 40% of patients still develop significant resistance (3,4). Therefore, how to overcome resistance to oxaliplatin is a key scientific problem to be solved in the treatment of metastatic colon cancers.Connexins are integral membrane proteins, six of which make up a hemi-channel. Two hemi-channels in neighboring cells dock together to form an integral gap junction (GJ). The GJ enables cells to exchange ions and small molecules (with a molecule weight less than 1 kDa) directly, including calcium, glutathione, cyclic adenosine monophosphate and cyclic guanosine monophosphate. Molecules transferred through the GJ are essential for numerous physiological and pathological events (5,6). The connexin gene family constitutes 21 isoforms, the most significant of which is Cx43 (6). The loss of Cx43 is extremely common in the development of cancers and is even involved in advanced stages of tumor progression. The deficiency of Cx43 also contributes to the resistance of chemotherapeutic agents (7). It has been...

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Section: Introductionsupporting

confidence: 70%

Deficiency of gap junction composed of connexin43 contributes to oxaliplatin resistance in colon cancer cells

Zhang

2017

Oncology Letters

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“…ROS exposure was measured by the 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA) method, and the procedure was performed as described before. 23 2.11 | RNA extraction and quantitative reverse transcription-polymerase chain reaction RNA extraction and reverse-transcription qRT-PCR were performed according to the manufacturer's protocol (Takara Bio Inc, Dalian, China). The primers used for HSP90 were as follows: 5′-AACACTAGCTGCTC CAAGGG-3′; 5′-GTAACTCATGGACGCAGGGG-3′.…”

Section: Measurement Of Ros Levelmentioning

confidence: 99%

17‐allylamino‐17‐demethoxygeldanamycin impeded chemotherapy through antioxidant activation via reducing reactive oxygen species‐induced cell death

Chen

Qiu

et al. 2018

J of Cellular Biochemistry

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Hyperthermia enhances the anticancer effects of thymidylate synthase (TYMS) inhibitors (raltitrexed, RTX) and improves the precise biochemical mechanisms partially through enhancement of intracellular drug absorption. Recent research focuses on the potential anticancer drug target Heat Shock Protein 90 (HSP90), which could increase the sensitivity of cancer cells to TYMS inhibitors; however, with different HSP90 inhibitors, several research studies finally showed a poor efficacy in preclinical or clinical research. Here, we showed that 17‐allylamino‐17‐demethoxygeldanamycin (17‐AAG, HSP90 inhibitor) affects the efficacy of chemotherapy through antioxidant activation–induced resistance. In this study, we found that RTX, alone or in combination with hyperthermia, triggers reactive oxygen species (ROS) exposure and thus induces cell death. Also, the addition of hyperthermia showed more ROS exposure and function. The pharmacologic inhibition of HSP90 reversed the effects of chemotherapeutical treatments, while the overexpression of HSP90 showed no relation with these effects, which demonstrated that dysregulation of HSP90 might have a significant impact on chemotherapeutic treatments. The addition of 17‐AAG increased the activation of antioxidant with increased antioxidant enzymes, thus affecting the RTX efficacy.

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“…The classic cancer therapy with chemotherapeutic agents is, among surgery, immunotherapy, radiation and targeted therapy, one of the central treatment strategies against neoplastic diseases. Platinum(II)-based agents are one group of anticancer drugs in chemotherapy, from which especially cisplatin ( cis -diamminedichloridoplatinum(II), CDDP) ( 1 ), carboplatin ( cis -diammine-1,1-cyclobutanedicarboxylatoplatinum(II), CBDCA) ( 2 ) and oxaliplatin ( trans - R , R -cyclohexane-1,2-diamineoxalateplatinum(II), 1-OHP) ( 3 ) ( Scheme 1 ) are used in a very high number of tumour chemotherapies [ 1 , 2 , 3 , 4 , 5 , 6 ]. All three mentioned Pt(II) complexes act via the formation of intrastrand and, to a lesser degree, interstrand DNA crosslinks after aquation and accompanied activation [ 4 , 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

“…CBDCA has been combined with 9-hydroxypheophorbide α (9-HPbD) and radachlorin, respectively, for the treatment of laryngeal cancer cells [ 18 , 19 , 20 ] as well as with verteporfin against ovarian [ 21 ] or Photofrin against cervical cancer cells [ 22 ]. 1-OHP has been used in a combined approach with hypericin in colorectal cancer cells [ 2 ]. All of these combinations led to enhanced cytotoxic effects and increased anticancer efficacy in vitro.…”

Section: Introductionmentioning

confidence: 99%

Evaluation for Synergistic Effects by Combinations of Photodynamic Therapy (PDT) with Temoporfin (mTHPC) and Pt(II) Complexes Carboplatin, Cisplatin or Oxaliplatin in a Set of Five Human Cancer Cell Lines

Lange

Bednarski

2018

IJMS

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The platinum(II) complexes carboplatin (CBDCA), cisplatin (CDDP) and oxaliplatin (1-OHP) are used as anticancer drugs in a large number of tumour chemotherapy regimens. Many attempts have been made to combine Pt(II)-based chemotherapy with alternative treatment strategies. One such alternative anticancer approach is known as photodynamic therapy (PDT), where a non-toxic photosensitizer (PS) produces oxidative stress via the formation of reactive oxygen species (ROS) after local illumination of the affected tissue. A very promising PS is 5,10,15,20-tetra(m-hydroxyphenyl)chlorin (mTHPC, Temoporfin), which is approved for the treatment of head and neck cancer in Europe. In the present study, a combination of mTHPC-mediated PDT and either CBDCA, CDDP, or 1-OHP was applied to five human cancer cell lines from different tumour origins. Cytotoxicity was determined by the MTT assay and synergistic effects on cytotoxicity were evaluated by calculation of Combination Indices (CI). Synergy was identified in some of the combinations, for example, with 1-OHP in three of the tested cell lines but antagonism was also observed for a number of combinations in certain cell lines. In cases of synergy, elevated ROS levels were observed after combination but apoptosis induction was not necessarily increased compared to a treatment with a single compound. Cell cycle analysis revealed a formation of apoptotic subG1 populations and S phase as well as G2/M phase arrests after combination. In conclusion, pre-treatment with mTHPC-PDT has the potential to sensitize some types of tumour cells towards Pt(II) complexes, in particular 1-OHP but synergy is highly dependent on the type of cancer.

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Enhancement of oxaliplatin sensitivity in human colorectal cancer by hypericin mediated photodynamic therapy via ROS-related mechanism

Cited by 41 publications

References 48 publications

Deficiency of gap junction composed of connexin43 contributes to oxaliplatin resistance in colon cancer cells

Deficiency of gap junction composed of connexin43 contributes to oxaliplatin resistance in colon cancer cells

17‐allylamino‐17‐demethoxygeldanamycin impeded chemotherapy through antioxidant activation via reducing reactive oxygen species‐induced cell death

Evaluation for Synergistic Effects by Combinations of Photodynamic Therapy (PDT) with Temoporfin (mTHPC) and Pt(II) Complexes Carboplatin, Cisplatin or Oxaliplatin in a Set of Five Human Cancer Cell Lines

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