Research Article
BibTex RIS Cite

Inhibition of Colorectal Cancer Cell Survival by Paclitaxel Combined with Olaparib

Year 2020, Volume: 10 Issue: 2, 427 - 440, 30.12.2020

Ramazan Gundogdu

https://doi.org/10.37094/adyujsci.737262

Abstract

Colorectal cancer is one of the main reasons for cancer-related mortality around the world and conventional chemotherapy approaches lead the clinical management of colorectal cancer treatment. Although many chemotherapeutics including paclitaxel have been effectively used to treat colorectal cancer patients, some tumour cells acquire drug resistance by increasing the regulation of various cellular mechanisms, primarily becoming addictive to some DNA repair activities. Preclinical evaluation of small-molecule inhibitors targeting various DNA damage response components is currently an active area of cancer research. This study aimed to assess the cytotoxic effect of paclitaxel combined with small-molecule PARP inhibitor olaparib in HCT116 colorectal cancer cells. We conducted clonogenic assays, showing that the paclitaxel and olaparib combination significantly inhibits the survival of colorectal cancer cells compared to paclitaxel or olaparib alone. By performing two distinct immunological methodology, Western blotting and immunofluorescence, we further demonstrated that olaparib intensifies the DNA damage accumulation induced by paclitaxel treatment. In conclusion, our preclinical study with HCT116 colorectal cancer cells suggests that olaparib may potentially serve as a combination partner to paclitaxel for effective colorectal cancer treatment.

Keywords

Colorectal cancer Paclitaxel treatment PARP inhibitors

Thanks

The author thanks Dr. M.K. Erdogan and S. Acikgoz for critical reading of the manuscript. The author further acknowledges the funding supports of the Scientific and Technological Research Council of Turkey (TUBITAK 119S007) and the Scientific Research Projects Coordination Unit of Bingol University (BAP-SHMYO.2019.00.002).

References

  • F. Bray, J. Ferlay, I. Soerjomataram, R. L. Siegel, L. A. Torre, and A. Jemal, Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries, CA. Cancer J. Clin., vol. 68, no. 6, pp. 394–424, Nov. 2018.
  • S. Ades, Adjuvant chemotherapy for colon cancer in the elderly: Moving from evidence to practice, Oncology, 2009.
  • N. F. Jensen et al., Establishment and characterization of models of chemotherapy resistance in colorectal cancer: Towards a predictive signature of chemoresistance, Mol. Oncol., 2015.
  • O. T., G. S., L. J.-B., T. A., M. T., K. M., T. Othman, S. Goto, J. B. Lee, A. Taimura, T. Matsumoto, and M. Kosaka, Hyperthermic enhancement of the apoptotic and antiproliferative activities of paclitaxel, Pharmacology, 2001.
  • A. M. Barbuti and Z. S. Chen, Paclitaxel through the ages of anticancer therapy: Exploring its role in chemoresistance and radiation therapy, Cancers. 2015.
  • A. J. J. Wood, E. K. Rowinsky, and R. C. Donehower, Paclitaxel (Taxol), New England Journal of Medicine. 1995.
  • A. Banerji, T. Lax, A. Guyer, S. Hurwitz, C. A. Camargo, and A. A. Long, Management of hypersensitivity reactions to carboplatin and paclitaxel in an outpatient oncology infusion center: A 5-year review, J. Allergy Clin. Immunol. Pract., 2014.
  • G. A. Orr, P. Verdier-Pinard, H. McDaid, and S. B. Horwitz, Mechanisms of Taxol resistance related to microtubules, Oncogene. 2003.
  • K. Lien, S. Georgsdottir, L. Sivanathan, K. Chan, and U. Emmenegger, Low-dose metronomic chemotherapy: A systematic literature analysis, Eur. J. Cancer, 2013.
  • D. Loven, E. Hasnis, F. Bertolini, and Y. Shaked, Low-dose metronomic chemotherapy: From past experience to new paradigms in the treatment of cancer, Drug Discovery Today. 2013.
  • L. H. Gong, X. X. Chen, H. Wang, Q. W. Jiang, S. S. Pan, J. G. Qiu, X. L. Mei, Y. Q. Xue, W. M. Qin, F. Y. Zheng, Z. Shi, and X. J. Yan, Piperlongumine induces apoptosis and synergizes with cisplatin or paclitaxel in human ovarian cancer cells, Oxid. Med. Cell. Longev., 2014.
  • C. Lv, H. Qu, W. Zhu, K. Xu, A. Xu, B. Jia, Y. Qing, H. Li, H. J. Wei, and H. Y. Zhao, Low-dose paclitaxel inhibits tumor cell growth by regulating glutaminolysis in colorectal carcinoma cells, Front. Pharmacol., 2017.
  • M. Cheng, H. H. Lee, W. H. Chang, N. R. Lee, H. Y. Huang, Y. J. Chen, H. C. Horng, W. L. Lee, and P. H. Wang, Weekly dose-dense paclitaxel and triweekly low-dose cisplatin: A well-tolerated and effective chemotherapeutic regimen for first-line treatment of advanced ovarian, fallopian tube, and primary peritoneal cancer, Int. J. Environ. Res. Public Health, 2019.
  • Q. Li, Z. Ma, Y. Liu, X. Kan, C. Wang, B. Su, Y. Li, Y. Zhang, P. Wang, Y. Luo, D. Na, L. Wang, G. Zhang, X. Zhu, and L. Wang, Low doses of paclitaxel enhance liver metastasis of breast cancer cells in the mouse model, FEBS J., 2016.
  • D. Shetti, B. Zhang, C. Fan, C. Mo, B. H. Lee, and K. Wei, Low Dose of Paclitaxel Combined with XAV939 Attenuates Metastasis, Angiogenesis and Growth in Breast Cancer by Suppressing Wnt Signaling, Cells, 2019.
  • A. Ciccia et al., The DNA Damage Response: Making It Safe to Play with Knives, Mol. Cell, vol. 40, no. 2, pp. 179–204, Oct. 2010.
  • M. Goldstein and M. B. Kastan, The DNA Damage Response: Implications for Tumor Responses to Radiation and Chemotherapy, Annu. Rev. Med., vol. 66, no. 1, pp. 129–143, Jan. 2015.
  • A. Sonnenblick, E. de Azambuja, H. A. Azim, and M. Piccart, An update on PARP inhibitors—moving to the adjuvant setting, Nat. Rev. Clin. Oncol., vol. 12, no. 1, pp. 27–41, Jan. 2015.
  • J. C. Morales, L. Li, F. J. Fattah, Y. Dong, E. A. Bey, M. Patel, J. Gao, and D. A. Boothman, Review of poly (ADP-ribose) polymerase (PARP) mechanisms of action and rationale for targeting in cancer and other diseases, Crit. Rev. Eukaryot. Gene Expr., 2014.
  • A. Dréan, C. J. Lord, and A. Ashworth, PARP inhibitor combination therapy, Crit. Rev. Oncol. Hematol., vol. 108, pp. 73–85, Dec. 2016.
  • C. Walsh, Targeted therapy for ovarian cancer: The rapidly evolving landscape of PARP inhibitor use, Minerva Ginecol., 2018.
  • The Food and Drug Administration (FDA), FDA approves olaparib for germline BRCA-mutated metastatic breast cancer, 2018. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-olaparib-germline-brca-mutated-metastatic-breast-cancer (accessed May 01, 2020).
  • The Food and Drug Administration (FDA), FDA approves olaparib for gBRCAm metastatic pancreatic adenocarcinoma, 2019. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-olaparib-gbrcam-metastatic-pancreatic-adenocarcinoma (accessed May 01, 2020).
  • S. Arena et al., A subset of colorectal cancers with cross-sensitivity to olaparib and oxaliplatin,” Clin. Cancer Res., 2020.
  • T. Augustine, R. Maitra, J. Zhang, J. Nayak, and S. Goel, Sensitization of colorectal cancer to irinotecan therapy by PARP inhibitor rucaparib, Invest. New Drugs, 2019.
  • S. M. Genther Williams, A. M. Kuznicki, P. Andrade, B. M. Dolinski, C. Elbi, R. C. O’Hagan, and C. Toniatti, Treatment with the PARP inhibitor, niraparib, sensitizes colorectal cancer cell lines to irinotecan regardless of MSI/MSS status, Cancer Cell Int., 2015.
  • V. Gomez, R. Gundogdu, M. Gomez, L. Hoa, N. Panchal, M. O’Driscoll, and A. Hergovich, Regulation of DNA damage responses and cell cycle progression by hMOB2., Cell. Signal., vol. 27, no. 2, pp. 326–39, Feb. 2015.
  • A. Hergovich, S. J. Bichsel, and B. A. Hemmings, Human NDR kinases are rapidly activated by MOB proteins through recruitment to the plasma membrane and phosphorylation., Mol. Cell. Biol., vol. 25, no. 18, pp. 8259–72, Sep. 2005.
  • B. A. Weaver, How Taxol/paclitaxel kills cancer cells, Molecular Biology of the Cell. 2014.
  • K. C. G. Berg, P. W. Eide, I. A. Eilertsen, B. Johannessen, J. Bruun, S. A. Danielsen, M. Bjørnslett, L. A. Meza-Zepeda, M. Eknæs, G. E. Lind, O. Myklebost, R. I. Skotheim, A. Sveen, and R. A. Lothe, Multi-omics of 34 colorectal cancer cell lines - a resource for biomedical studies, Mol. Cancer, 2017.
  • M. P. Duldulao, W. Lee, M. Le, Z. Chen, W. Li, J. Wang, H. Gao, H. Li, J. Kim, and J. Garcia-Aguilar, Gene expression variations in microsatellite stable and unstable colon cancer cells, J. Surg. Res., 2012.
  • L. J. Kuo and L. X. Yang, γ-H2AX- A novel biomaker for DNA double-strand breaks, In Vivo. 2008.
  • A. Desai, Y. Yan, and S. L. Gerson, Advances in therapeutic targeting of the DNA damage response in cancer, 2018.
  • M. Masutani, T. Nozaki, K. Wakabayashi, and T. Sugimura, Role of poly(ADP-ribose) polymerase in cell-cycle checkpoint mechanisms following γ-irradiation, Biochimie, 1995.
  • T. Ollikainen, A. Knuuttila, S. Suhonen, M. Taavitsainen, A. Jekunen, K. Mattson, and K. Linnainmaa, In vitro sensitivity of normal human mesothelial and malignant mesothelioma cell lines to four new chemotherapeutic agents, Anticancer. Drugs, 2000.
  • L. Digue, T. Orsière, M. De Méo, M. G. Mattéi, D. Depetris, F. Duffaud, R. Favre, and A. Botta, Evaluation of the genotoxic activity of paclitaxel by the in vitro micronucleus test in combination with fluorescent in situ hybridization of a DNA centromeric probe and the alkaline single cell gel electrophoresis technique (comet assay) in human T-lymph, Environ. Mol. Mutagen., 1999.
  • M. T. Branham, S. B. Nadin, L. M. Vargas-Roig, and D. R. Ciocca, DNA damage induced by paclitaxel and DNA repair capability of peripheral blood lymphocytes as evaluated by the alkaline comet assay, Mutat. Res. - Genet. Toxicol. Environ. Mutagen., 2004.
  • H. E. Bryant and T. Helleday, Inhibition of poly (ADP-ribose) polymerase activates ATM which is required for subsequent homologous recombination repair, Nucleic Acids Res., 2006.

HCT116 Kolorektal Kanser Hücre Sağ-kalımının Paklitaksel ve Olaparib Kombinasyon Tedavisiyle Engellenmesi

Year 2020, Volume: 10 Issue: 2, 427 - 440, 30.12.2020

Ramazan Gundogdu

https://doi.org/10.37094/adyujsci.737262

Abstract

Kolorektal kanser, dünya genelinde kansere bağlı ölümün temel sebeplerinden biridir ve konvansiyonel kemoterapi yaklaşımları kolorektal kanser tedavisinin klinik yönetimine öncülük etmektedir. Paklitaksel dahil olmak üzere çoğu kemoterapötik, kolorektal kanser hastalarını tedavi etmede etkili bir şekilde kullanılmasına rağmen, bazı tümör hücreleri özellikle çeşitli DNA tamir aktivitelerine bağımlılık kazanmak suretiyle çok sayıda hücresel mekanizmaların düzenlenmesini arttırarak ilaç direnci kazanırlar. Çeşitli DNA hasar yanıtı bileşenlerini hedefleyen küçük-moleküllü inhibitörlerin klinik öncesi değerlendirmesi günümüzde kanser araştırmalarının aktif bir alanını oluşturmaktadır. Bu çalışma, HCT116 kolorektal kanser hücrelerinde paklitaksel ile kombine edilen küçük-moleküllü PARP inhibitörü olaparibin sitotoksik etkisini değerlendirmeyi amaçlamıştır. Gerçekleştirdiğimiz koloni sağ-kalım analizleri paklitaksel ve olaparib kombinasyonunun sadece paklitaksel ya da olaparib tedavisi ile kıyas edildiğinde kolorektal kanser hücrelerinin sağ kalımını önemli derecede inhibe ettiğini gösterdi. Western blot ve immünofloresan olmak üzere iki farklı immünolojik yöntem gerçekleştirilerek, olaparibin paklitaksel tedavisinin oluşturduğu DNA hasarı birikimini yoğunlaştırdığı tespit edildi. Sonuç olarak, HCT116 kolorektal kanser hücreleriyle gerçekleştirdiğimiz klinik öncesi çalışmamız, olaparib ve paklitaksel kombinasyonunun kolorektal kanser tedavisi için potansiyel bir tedavi yaklaşımı sunabileceğini göstermektedir.

Keywords

Kolorektal kanser Paklitaksel tedavisi PARP inhibitörleri

References

  • F. Bray, J. Ferlay, I. Soerjomataram, R. L. Siegel, L. A. Torre, and A. Jemal, Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries, CA. Cancer J. Clin., vol. 68, no. 6, pp. 394–424, Nov. 2018.
  • S. Ades, Adjuvant chemotherapy for colon cancer in the elderly: Moving from evidence to practice, Oncology, 2009.
  • N. F. Jensen et al., Establishment and characterization of models of chemotherapy resistance in colorectal cancer: Towards a predictive signature of chemoresistance, Mol. Oncol., 2015.
  • O. T., G. S., L. J.-B., T. A., M. T., K. M., T. Othman, S. Goto, J. B. Lee, A. Taimura, T. Matsumoto, and M. Kosaka, Hyperthermic enhancement of the apoptotic and antiproliferative activities of paclitaxel, Pharmacology, 2001.
  • A. M. Barbuti and Z. S. Chen, Paclitaxel through the ages of anticancer therapy: Exploring its role in chemoresistance and radiation therapy, Cancers. 2015.
  • A. J. J. Wood, E. K. Rowinsky, and R. C. Donehower, Paclitaxel (Taxol), New England Journal of Medicine. 1995.
  • A. Banerji, T. Lax, A. Guyer, S. Hurwitz, C. A. Camargo, and A. A. Long, Management of hypersensitivity reactions to carboplatin and paclitaxel in an outpatient oncology infusion center: A 5-year review, J. Allergy Clin. Immunol. Pract., 2014.
  • G. A. Orr, P. Verdier-Pinard, H. McDaid, and S. B. Horwitz, Mechanisms of Taxol resistance related to microtubules, Oncogene. 2003.
  • K. Lien, S. Georgsdottir, L. Sivanathan, K. Chan, and U. Emmenegger, Low-dose metronomic chemotherapy: A systematic literature analysis, Eur. J. Cancer, 2013.
  • D. Loven, E. Hasnis, F. Bertolini, and Y. Shaked, Low-dose metronomic chemotherapy: From past experience to new paradigms in the treatment of cancer, Drug Discovery Today. 2013.
  • L. H. Gong, X. X. Chen, H. Wang, Q. W. Jiang, S. S. Pan, J. G. Qiu, X. L. Mei, Y. Q. Xue, W. M. Qin, F. Y. Zheng, Z. Shi, and X. J. Yan, Piperlongumine induces apoptosis and synergizes with cisplatin or paclitaxel in human ovarian cancer cells, Oxid. Med. Cell. Longev., 2014.
  • C. Lv, H. Qu, W. Zhu, K. Xu, A. Xu, B. Jia, Y. Qing, H. Li, H. J. Wei, and H. Y. Zhao, Low-dose paclitaxel inhibits tumor cell growth by regulating glutaminolysis in colorectal carcinoma cells, Front. Pharmacol., 2017.
  • M. Cheng, H. H. Lee, W. H. Chang, N. R. Lee, H. Y. Huang, Y. J. Chen, H. C. Horng, W. L. Lee, and P. H. Wang, Weekly dose-dense paclitaxel and triweekly low-dose cisplatin: A well-tolerated and effective chemotherapeutic regimen for first-line treatment of advanced ovarian, fallopian tube, and primary peritoneal cancer, Int. J. Environ. Res. Public Health, 2019.
  • Q. Li, Z. Ma, Y. Liu, X. Kan, C. Wang, B. Su, Y. Li, Y. Zhang, P. Wang, Y. Luo, D. Na, L. Wang, G. Zhang, X. Zhu, and L. Wang, Low doses of paclitaxel enhance liver metastasis of breast cancer cells in the mouse model, FEBS J., 2016.
  • D. Shetti, B. Zhang, C. Fan, C. Mo, B. H. Lee, and K. Wei, Low Dose of Paclitaxel Combined with XAV939 Attenuates Metastasis, Angiogenesis and Growth in Breast Cancer by Suppressing Wnt Signaling, Cells, 2019.
  • A. Ciccia et al., The DNA Damage Response: Making It Safe to Play with Knives, Mol. Cell, vol. 40, no. 2, pp. 179–204, Oct. 2010.
  • M. Goldstein and M. B. Kastan, The DNA Damage Response: Implications for Tumor Responses to Radiation and Chemotherapy, Annu. Rev. Med., vol. 66, no. 1, pp. 129–143, Jan. 2015.
  • A. Sonnenblick, E. de Azambuja, H. A. Azim, and M. Piccart, An update on PARP inhibitors—moving to the adjuvant setting, Nat. Rev. Clin. Oncol., vol. 12, no. 1, pp. 27–41, Jan. 2015.
  • J. C. Morales, L. Li, F. J. Fattah, Y. Dong, E. A. Bey, M. Patel, J. Gao, and D. A. Boothman, Review of poly (ADP-ribose) polymerase (PARP) mechanisms of action and rationale for targeting in cancer and other diseases, Crit. Rev. Eukaryot. Gene Expr., 2014.
  • A. Dréan, C. J. Lord, and A. Ashworth, PARP inhibitor combination therapy, Crit. Rev. Oncol. Hematol., vol. 108, pp. 73–85, Dec. 2016.
  • C. Walsh, Targeted therapy for ovarian cancer: The rapidly evolving landscape of PARP inhibitor use, Minerva Ginecol., 2018.
  • The Food and Drug Administration (FDA), FDA approves olaparib for germline BRCA-mutated metastatic breast cancer, 2018. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-olaparib-germline-brca-mutated-metastatic-breast-cancer (accessed May 01, 2020).
  • The Food and Drug Administration (FDA), FDA approves olaparib for gBRCAm metastatic pancreatic adenocarcinoma, 2019. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-olaparib-gbrcam-metastatic-pancreatic-adenocarcinoma (accessed May 01, 2020).
  • S. Arena et al., A subset of colorectal cancers with cross-sensitivity to olaparib and oxaliplatin,” Clin. Cancer Res., 2020.
  • T. Augustine, R. Maitra, J. Zhang, J. Nayak, and S. Goel, Sensitization of colorectal cancer to irinotecan therapy by PARP inhibitor rucaparib, Invest. New Drugs, 2019.
  • S. M. Genther Williams, A. M. Kuznicki, P. Andrade, B. M. Dolinski, C. Elbi, R. C. O’Hagan, and C. Toniatti, Treatment with the PARP inhibitor, niraparib, sensitizes colorectal cancer cell lines to irinotecan regardless of MSI/MSS status, Cancer Cell Int., 2015.
  • V. Gomez, R. Gundogdu, M. Gomez, L. Hoa, N. Panchal, M. O’Driscoll, and A. Hergovich, Regulation of DNA damage responses and cell cycle progression by hMOB2., Cell. Signal., vol. 27, no. 2, pp. 326–39, Feb. 2015.
  • A. Hergovich, S. J. Bichsel, and B. A. Hemmings, Human NDR kinases are rapidly activated by MOB proteins through recruitment to the plasma membrane and phosphorylation., Mol. Cell. Biol., vol. 25, no. 18, pp. 8259–72, Sep. 2005.
  • B. A. Weaver, How Taxol/paclitaxel kills cancer cells, Molecular Biology of the Cell. 2014.
  • K. C. G. Berg, P. W. Eide, I. A. Eilertsen, B. Johannessen, J. Bruun, S. A. Danielsen, M. Bjørnslett, L. A. Meza-Zepeda, M. Eknæs, G. E. Lind, O. Myklebost, R. I. Skotheim, A. Sveen, and R. A. Lothe, Multi-omics of 34 colorectal cancer cell lines - a resource for biomedical studies, Mol. Cancer, 2017.
  • M. P. Duldulao, W. Lee, M. Le, Z. Chen, W. Li, J. Wang, H. Gao, H. Li, J. Kim, and J. Garcia-Aguilar, Gene expression variations in microsatellite stable and unstable colon cancer cells, J. Surg. Res., 2012.
  • L. J. Kuo and L. X. Yang, γ-H2AX- A novel biomaker for DNA double-strand breaks, In Vivo. 2008.
  • A. Desai, Y. Yan, and S. L. Gerson, Advances in therapeutic targeting of the DNA damage response in cancer, 2018.
  • M. Masutani, T. Nozaki, K. Wakabayashi, and T. Sugimura, Role of poly(ADP-ribose) polymerase in cell-cycle checkpoint mechanisms following γ-irradiation, Biochimie, 1995.
  • T. Ollikainen, A. Knuuttila, S. Suhonen, M. Taavitsainen, A. Jekunen, K. Mattson, and K. Linnainmaa, In vitro sensitivity of normal human mesothelial and malignant mesothelioma cell lines to four new chemotherapeutic agents, Anticancer. Drugs, 2000.
  • L. Digue, T. Orsière, M. De Méo, M. G. Mattéi, D. Depetris, F. Duffaud, R. Favre, and A. Botta, Evaluation of the genotoxic activity of paclitaxel by the in vitro micronucleus test in combination with fluorescent in situ hybridization of a DNA centromeric probe and the alkaline single cell gel electrophoresis technique (comet assay) in human T-lymph, Environ. Mol. Mutagen., 1999.
  • M. T. Branham, S. B. Nadin, L. M. Vargas-Roig, and D. R. Ciocca, DNA damage induced by paclitaxel and DNA repair capability of peripheral blood lymphocytes as evaluated by the alkaline comet assay, Mutat. Res. - Genet. Toxicol. Environ. Mutagen., 2004.
  • H. E. Bryant and T. Helleday, Inhibition of poly (ADP-ribose) polymerase activates ATM which is required for subsequent homologous recombination repair, Nucleic Acids Res., 2006.
There are 38 citations in total.

Details

Primary Language English
Subjects Structural Biology
Journal Section Biology
Authors

Ramazan Gundogdu 0000-0001-5230-2121

Publication Date December 30, 2020
Submission Date May 14, 2020
Acceptance Date October 22, 2020
Published in Issue Year 2020 Volume: 10 Issue: 2

Cite

APA Gundogdu, R. (2020). Inhibition of Colorectal Cancer Cell Survival by Paclitaxel Combined with Olaparib. Adıyaman University Journal of Science, 10(2), 427-440. https://doi.org/10.37094/adyujsci.737262
AMA Gundogdu R. Inhibition of Colorectal Cancer Cell Survival by Paclitaxel Combined with Olaparib. ADYU J SCI. December 2020;10(2):427-440. doi:10.37094/adyujsci.737262
Chicago Gundogdu, Ramazan. “Inhibition of Colorectal Cancer Cell Survival by Paclitaxel Combined With Olaparib”. Adıyaman University Journal of Science 10, no. 2 (December 2020): 427-40. https://doi.org/10.37094/adyujsci.737262.
EndNote Gundogdu R (December 1, 2020) Inhibition of Colorectal Cancer Cell Survival by Paclitaxel Combined with Olaparib. Adıyaman University Journal of Science 10 2 427–440.
IEEE R. Gundogdu, “Inhibition of Colorectal Cancer Cell Survival by Paclitaxel Combined with Olaparib”, ADYU J SCI, vol. 10, no. 2, pp. 427–440, 2020, doi: 10.37094/adyujsci.737262.
ISNAD Gundogdu, Ramazan. “Inhibition of Colorectal Cancer Cell Survival by Paclitaxel Combined With Olaparib”. Adıyaman University Journal of Science 10/2 (December 2020), 427-440. https://doi.org/10.37094/adyujsci.737262.
JAMA Gundogdu R. Inhibition of Colorectal Cancer Cell Survival by Paclitaxel Combined with Olaparib. ADYU J SCI. 2020;10:427–440.
MLA Gundogdu, Ramazan. “Inhibition of Colorectal Cancer Cell Survival by Paclitaxel Combined With Olaparib”. Adıyaman University Journal of Science, vol. 10, no. 2, 2020, pp. 427-40, doi:10.37094/adyujsci.737262.
Vancouver Gundogdu R. Inhibition of Colorectal Cancer Cell Survival by Paclitaxel Combined with Olaparib. ADYU J SCI. 2020;10(2):427-40.
 Download Cover Image

...