Targeting autophagy reverses de novo resistance in homologous recombination repair proficient breast cancers to PARP inhibition

Background Poly(ADP-ribose) polymerase inhibitors (PARPi) target tumours defective in homologous recombination (HR). Most BRCA-wild-type (WT) HR-proficient breast cancers are intrinsically resistant to PARP inhibitors, e.g., talazoparib. We evaluated the role of autophagy in this de novo resistance and determined the underlying mechanism to overcome this.Methods Autophagosome formation and autophagic flux were assessed by evaluating endogenous LC3-II levels and ectopic expression of EGFP-LC3 and mRFP-EGFP-LC3 in breast cancer cells. Autophagy-defective cells were generated by genetic depletion of BECN1, ATG5, p62/SQSTM1 and LAMP1 by using CRISPR-Cas9 double nickase system. The response of PARPi was evaluated in autophagy-proficient and -defective breast cancer cells and in xenograft SCID-mice model.Results Pro-survival autophagy was significantly enhanced upon talazoparib treatment in BRCA-WT breast cancer cell lines. Autophagy-deficient cells were hypersensitive to talazoparib. Targeting autophagy synergistically enhanced the therapeutic efficacy of talazoparib in BRCA1-WT breast cancer cells in vitro and in vivo xenograft tumour mouse model. Mechanistically, autophagy inhibition by chloroquine promoted deleterious NHEJ mediated DSB-repair, leading to extensive genomic instability and mitotic catastrophe.Conclusions Autophagy confers de novo resistance to PARP inhibitor, talazoparib. Autophagy inhibition improves the therapeutic outcome of PARPi treatment in preclinical mice model, bearing HR-proficient breast tumours, warranting its usage in the clinical settings.Subject terms: Breast cancer, Cancer therapy     

Antimelanoma Potential of Eruca sativa Seed Oil and its Bioactive Principles

The present communication reports the comparison of in vivo antioxidant, antimelanoma and antimutagenic activities of Eruca sativa seed oil and its bio principles (allyl isothiocyanate, phenylethyl isothiocyanate and sulphoraphane) against B16F10 melanoma cells induced in C57BL/6 mice model. Among the various treatments considered for the study, isothiocyanates combination (allyl isothiocyanate, phenylethyl isothiocyanate and sulphoraphane; 1:1:1; 10 µM) exhibited optimum antioxidant activity, 51.95±1.14 µM glutathione per mg protein compared to seed oil 25.91±1.26 µM. Lipid peroxidation value was 9.97±1.72 µM malondialdehyde per mg wet weight for isothiocyanates combination against seed oil, 28.45±1.87 µM and rendered significant protection against oxidative stress induced by melanoma in liver tissue. Isothiocyanates combination significantly suppressed various parameters, such as tumor growth, isothiocyanates combination by 36.36% while the seed oil by 15.23%; tumor weight, isothiocyanates combination by 45.9% and seed oil by 19.6%; tumor volume, isothiocyanates combination by 41.7% while the seed oil by 32.3%, measured for antimelanoma activity at a concentration of 10 µM. Isothiocyanates combination has been found to be more cytotoxic bioagent against B16F10 melanoma cells induced in C57BL/6 mice compared to naturally occurring Eruca sativa seed oil.     

Management of cap striae following challenging small incision lenticule extraction surgery – A case report

A 24-year-old female underwent small incision lenticule extraction (SMILE) for myopic astigmatism OU. In the left eye, cap-lenticular adhesion along with tearing of the cap occurred, resulting in a gaped incision and transverse striae involving the visual axis on the first post op day. Uncorrected distance visual acuity (UDVA) was 20/32. The case was managed with interface wash and stretching of the cap, in order to iron out the striae. Post intervention, the UDVA improved to 20/20, striae resolved, and interface remained clear through a follow-up of nine months, suggesting that cap striae in SMILE may be similarly managed as the flap striae in laser-assisted in situ keratomileusis (LASIK), resulting in satisfactory visual outcomes.