Optimal Delivery of Cytotoxic Chemotherapy for Colon Cancer

Raftery, Laura; Goldberg, Richard M.

doi:10.1097/ppo.0b013e3181ddc5ac

Cited by 25 publications

(15 citation statements)

References 44 publications

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“…Colon cancer is currently treated with 5-flourouracil and oxaliplatin. 11 However, while synthetic chemical anticancer drugs prolong survival, they often have adverse effects and off target actions. Accordingly, there is a need to develop novel drug therapies for colon cancer.…”

Section: Discussionmentioning

confidence: 99%

Cytotoxic Effect of Caralluma fimbriata Against Human Colon Cancer Cells

Ashwini¹,

Ezhilarasan²,

Anitha³

2017

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Aim: The present study was designed to examine the cytotoxic effects of ethanolic leaf extract of Caralluma fimbriata in the COLO 320 cell line. Materials and Method: The anti-proliferative effects were evaluated using the MTT assay. The COLO 320 cells were treated with different concentrations of the leaf extract of Caralluma (100 -300 µg/ml) for 24 h. The cell viability and IC 50 was calculated from the cytotoxicity. The morphology of the Caralluma treated cells, control, and positive control were observed under reverse phase inverted microscope. Result: The C. fimbriata ethanolic leaf extract showed dose dependant increase in cytotoxicity in COLO 320 human colon cancer cells. The maximum cytotoxic effect was noticed with maximum dose used in this study i.e., 300 µg with an IC 50 value of 233.87 µg. Conclusion: The present study shows that the ethanolic leaf extract of Caralluma fimbriata is capable of reducing cell proliferation by inducing cytotoxicity of COLO 320 cells.

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Section: Discussionmentioning

confidence: 99%

Cytotoxic Effect of Caralluma fimbriata Against Human Colon Cancer Cells

Ashwini¹,

Ezhilarasan²,

Anitha³

2017

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“…Because of its' relative toxicity to proliferating cells, SN38 is a major drug used in either first line (Xeliri (Capecitabine/irinotecan)/ Folfiri (leucovorin/5-FU/irinotecan)) or second line (Xeliri/ Folfiri or irinotecan alone) treatment of metastatic colon cancer. Problematically, response rates to this drug are less than 50% and the duration of response is less than 1 year [10].…”

Section: Introductionmentioning

confidence: 99%

Irinotecan and DNA-PKcs inhibitors synergize in killing of colon cancer cells

et al. 2011

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This study sought to measure the degree of synergy induced by specific small molecule inhibitors of DNA-PK [NU7026 and IC486241 (ICC)], a major component of the non-homologous end-joining (NHEJ) pathway, with SN38 or oxaliplatin. Synergy between the DNA damaging drugs and the DNA-PK inhibitors was assessed using the sulforhodamine-B assay (SRB). Effects of drug combinations on cell cycle and DNA-PK activity were determined using flow cytometry and western blot analysis. DNA damage was assessed via comet assay and quantification of γH2AX. The role of homologous recombination repair (HRR) was determined by nuclear Rad51 protein levels and a GFP reporter recombination assay. Significant reductions in the IC(50) values of SN38 were observed at 5 and 10 μM of DNA-PK inhibitors. Moreover, at 1-2 μM (attainable concentrations with ICC in mice) these DNA-PKcs inhibitors demonstrated synergistic reductions in the IC(50) of SN38. Flow cytometric data indicated that SN38 and SN38 in combination with DNA-PKcs inhibitors showed dramatic G2/M arrest at 24 h. Furthermore, reduced phosphorylation of DNA-PKcs and increased DNA damage were observed at this time point with SN38 in combination with DNA-PKcs inhibitors as compared to cells treated with SN38 alone. SN38 alone and in the presence of ICC increased nuclear Rad51 protein levels. Furthermore, inhibition of DNA-PKcs increased HRR suggesting that NHEJ is a negative regulator of HRR. These data indicate that small molecule inhibitors of DNA-PKcs dramatically enhance the efficacy of SN38 in colon cancer cell lines.

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“…Current chemotherapeutic regimens for the treatment of metastatic colon cancer include the DNA damaging drugs, oxaliplatin or irinotecan, in combination with the nucleotide analog 5FU [1]. Although these treatments are initially effective in many patients, all patients eventually become resistant.…”

Section: Introductionmentioning

confidence: 99%

“…Metastatic colon cancer related mortality remains high due to the development of drug resistance over the course of treatment [1]. Current chemotherapeutic regimens for the treatment of metastatic colon cancer include the DNA damaging drugs, oxaliplatin or irinotecan, in combination with the nucleotide analog 5FU [1].…”

Section: Introductionmentioning

confidence: 99%

The PARP inhibitor ABT-888 synergizes irinotecan treatment of colon cancer cell lines

et al. 2012

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Poly [ADP-ribose] polymerase-1 (PARP-1) localizes rapidly to sites of DNA damage and has been associated with various repair mechanisms including base excision repair (BER) and homologous recombination/non-homologous end joining (HRR/NHEJ). PARP-1 acts by adding poly-ADP ribose side chains to target proteins (PARylation) altering molecular interactions and functions. Recently small molecule inhibitors of PARP-1 have been shown to have significant clinical potential and third generation PARP inhibitors are currently being investigated in clinical trials. These drugs alone or in combination with radio/chemotherapy have resulted in meaningful patient responses and an increase in survival in metastatic breast cancer cases bearing BRCA-deficient or triple negative tumors and BRCA-deficient ovarian cancer patients. ABT-888, a potent PARP-1 inhibitor, sensitizes many cancer cells in-vitro and in-vivo to temozolomide. As such, we hypothesized that colon cancers would be sensitized to the DNA damaging chemotherapeutic agents, oxaliplatin and irinotecan, by ABT-888. Using colon cancer cell lines significant synergy was observed between ABT-888 and irinotecan at concentrations of ABT-888 as low as 0.125 μM. The level of synergy observed correlated with the degree of PARP1 inhibition as measured biochemically in cell lysates. ABT-888 at concentrations of 0.5-4 μM resulted in synergy with oxaliplatin. Furthermore, 24 h post treatment combinations of ABT-888/irinotecan generally resulted in increased G2/M cell cycle arrest and increased levels of DNA damage, followed by increased levels of apoptosis 48 h post treatment. In conclusion this study suggests that ABT-888 may be a clinically effective adjuvant to current colon cancer therapies that include the use of irinotecan and/or oxaliplatin.

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Optimal Delivery of Cytotoxic Chemotherapy for Colon Cancer

Cited by 25 publications

References 44 publications

Cytotoxic Effect of Caralluma fimbriata Against Human Colon Cancer Cells

Cytotoxic Effect of Caralluma fimbriata Against Human Colon Cancer Cells

Irinotecan and DNA-PKcs inhibitors synergize in killing of colon cancer cells

The PARP inhibitor ABT-888 synergizes irinotecan treatment of colon cancer cell lines

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