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Reversal of boswellic acid analog BA145 induced caspase dependent apoptosis by PI3K inhibitor LY294002 and MEK inhibitor PD98059

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Abstract

PI3K/Akt and ERK pathways are important for growth and proliferation of many types of cancers. Therefore, PI3K inhibitor LY294002 (LY) and MEK1/2 inhibitor PD98059 (PD) are used to sensitize many types of cancer cell lines to chemotherapeutic agents, where AKT and ERK pathways are over activated. However, in this study, we show for the first time that PD could protect the leukemia cells independent of ERK pathway inhibition, besides, we also report a detailed mechanism for antiapoptotic effect of LY in HL-60 cells against the cytotoxicity induced by a boswellic acid analog BA145. Apoptosis induced by BA145 is accompanied by downregulation of PI3K/Akt and ERK pathways in human myelogenous leukemia HL-60 cells, having activating N-Ras mutation. Both LY and PD protected the cells against mitochondrial stress caused by BA145, and reduced the release of cytochrome c and consequent activation of caspase-9. LY and PD also diminished the activation of caspase-8 without affecting the death receptors. Besides, LY and PD also reversed the caspase dependent DNA damage induced by BA145. Further studies revealed that LY and PD significantly reversed the inhibitory effect of BA145 on cell cycle regulatory proteins by upregulating hyperphosphorylated retinoblastoma, pRB (S795) and downregulating p21 and cyclin E. More importantly, all these events were reversed by caspase inhibition by Z-VAD-fmk, suggesting that both LY and PD act at the level of caspases to diminish the apoptosis induced by BA145. These results indicate that inhibitors of PI3K/Akt and ERK pathways can play dual role and act against chemotherapeutic agents.

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Acknowledgments

We are thankful to the Council of Scientific and Industrial Research (CSIR), India, for providing financial help for this study. Thanks are also due to University Grants Commission, India, for providing Senior Research Fellowship to Suresh Kumar.

Conflict of interest

The authors declare no conflict of interest.

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Authors and Affiliations

  1. Academy of Scientific and Innovative Research, CSIR, New Delhi, India

    Anup S. Pathania & Fayaz A. Malik

  2. Divisions of Cancer Pharmacology, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu, 180001, India

    Anup S. Pathania, Suresh Kumar, Santosh K. Guru, Shashi Bhushan, Parduman R. Sharma, Ajit K. Saxena, Jaswant Singh, Fayaz A. Malik & Ajay Kumar

  3. Department of Biotechnology, SGGS College, Sector-26, Chandigarh, 160019, India

    Amit Joshi

  4. Divisions of Plant Biotechnology, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu, 180001, India

    Wajid W. Bhat

  5. Divisions of Natural Products Microbes, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu, 180001, India

    Bhahwal A. Shah, Samar S. Andotra & Subhash C. Taneja

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  1. Anup S. Pathania
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Correspondence to Fayaz A. Malik or Ajay Kumar.

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Pathania, A.S., Joshi, A., Kumar, S. et al. Reversal of boswellic acid analog BA145 induced caspase dependent apoptosis by PI3K inhibitor LY294002 and MEK inhibitor PD98059. Apoptosis 18, 1561–1573 (2013). https://doi.org/10.1007/s10495-013-0889-4

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  • DOI: https://doi.org/10.1007/s10495-013-0889-4

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