80P - Steroidal oximes: A new potential therapeutic approach for cancer treatment

Background

Cancer still remains one of the life-threatening diseases worldwide despite the large number of therapeutic approaches currently available. Steroidal compounds possess numerous biological activities being antitumor one of them. Oximes have also been associated with antitumor activity. Moreover, previous studies by our group demonstrated that steroidal oximes were also very potent against several types of cancer. Thus, we embarked in the design and synthesis of new steroidal oximes and evaluated their potential antitumor activity against lung, prostate, and triple-negative breast cancer cells, with the aim of finding alternative cytotoxic compounds for cancer treatment.

Methods

Compounds OX1, OX2, ExeOx and Formox and their parent compounds P1, OL2, Exe and Form were synthesized, and their cytotoxicity evaluated in H1299, PC3 and HCC1806 cell lines through SRB assay after the treatment of the cells with the compounds (1-75 μM). Cell viability, cell death profile, alterations on cell cycle and mitochondrial membrane potential were assessed by flow cytometry.

Results

All compounds decreased H1299, PC3 and HCC1806 cancer cell proliferation in a dose-dependent manner, with the exception of OX2. Overall, the parent compounds decreased cancer cell proliferation in a less pronounced way, proving that the introduction of an oxime group was beneficial for the cytotoxicity displayed. Moreover, the best compound was OX1 in all cell lines with IC₅₀ values of 18.69, 22.90 and 29.95 μM in H1299, HCC1806 and PC3, respectively. Flow cytometry studies with OX1 showed that this compound was able to decrease cell viability in all cell lines by causing cell death mainly by apoptosis, which was accompanied by a blockage at phases G2/M and S, depending on the cell line. Considering the mitochondrial membrane potential, OX1 induced mitochondrial dysfunction, which might also be related to apoptosis.

Conclusions

Our results show that OX1 possesses a beneficial antitumor effect from the introduction of the oxime group, which is mediated by apoptosis. This effect encourages further studies on its mechanism of action and selectivity in order to discover new molecules for cancer treatment.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Univ Coimbra.

Funding

Foundation for Science and Technology (FCT), Portugal (Strategic Projects UID/NEU/04539/2019, UIDB/04539/2020, UIDP/04539/2020); COMPETE-FEDER (POCI-01-0145-FEDER-007440); PhD Fellowship from FCT and European Social Funding of Ana R. Gomes (UI/BD/150865/2021).

Disclosure

All authors have declared no conflicts of interest.